Durability of the Clinical Benefit of Droxidopa for Neurogenic Orthostatic Hypotension During 12 Weeks of Open-Label Treatment.

INTRODUCTION: Droxidopa is approved to treat neurogenic orthostatic hypotension (nOH) symptoms in patients with autonomic failure based on short-term clinical trial data. Additional data on the long-term efficacy of droxidopa are needed. We have evaluated the 12-week efficacy and tolerability of droxidopa in patients with nOH in an open-label period of an ongoing phase 4 study . METHODS: Patients received 12 weeks of open-label treatment with an individually optimized droxidopa dose (100-600 mg, 3 times daily) as identified during a preceding titration period. Patient-reported outcomes included the Orthostatic Hypotension Symptom Assessment (OHSA), Orthostatic Hypotension Daily Activity Scale (OHDAS), and clinician- and patient-rated Clinical Global Impression-Severity (CGI-S) scales. Supine blood pressure (BP) and adverse events (AEs) were recorded. RESULTS: Data from 114 patients enrolled into the 12-week open-label period were available for analyses. After 12 weeks of droxidopa treatment, patients reported significant (P < 0.0001) improvements from baseline in OHSA and OHDAS composite and individual item scores and on clinician and patient CGI-S scores. Mean ± SD supine systolic and diastolic BP at week 12 increased by 15.5 ± 22.9 and 7.8 ± 11.7 mmHg from baseline, respectively (P < 0.0001 for both). The most frequently reported AEs were falls (17%), headache (13%), and dizziness (9%); one (0.9%) patient reported an AE of supine hypertension. CONCLUSION: During 12 weeks of open-label treatment, droxidopa was associated with significant improvement from baseline in nOH symptoms and activities of daily living. No clinically important changes in supine hypertension or AEs of concern were observed. These results support the efficacy of droxidopa beyond 2 weeks of treatment. TRIAL REGISTRATION: NCT02586623.

Psychometric validation of a patient-reported single-item assessment of 'Good Day Bad Day' in a neurogenic orthostatic hypotension population treated with droxidopa.

BACKGROUND: Symptoms of neurogenic orthostatic hypotension (nOH), including lightheadedness/dizziness, presyncope, syncope, and falls, can lead to impaired functional ability and reduced quality of life. Because the severity and frequency of nOH symptoms fluctuate, it may be difficult for patients to accurately quantify the effect of symptoms on their daily lives using available outcome measures. A new single-item instrument, the 'Good Day Bad Day,' was developed, and its psychometric validity was assessed in patients with nOH. METHODS: Data from a 6-month, prospective, observational cohort study of patients with nOH who were newly initiating droxidopa treatment were used. Patients were asked to quantify the number of good and bad days in the previous 7 days and responded to other validated patient-reported outcomes instruments. The concurrent and discriminant validities and the stability of the Good Day Bad Day instrument were assessed. RESULTS: A total of 153 patients were included in the analysis (mean [SD] age, 62.3 [17] years). Change in the number of good days moderately correlated with improvements in other patient-reported outcomes (rho value range, -0.38 to -0.61). When data were examined categorically (low vs high symptom severity), the mean number of good days was higher in subgroups representing low symptom severity across measures at 1, 3, and 6 months (all P ≤ 0.01). CONCLUSIONS: The Good Day Bad Day instrument provided good discrimination at baseline and over time and may aid in assessment of the effects of nOH symptoms on patients.

Characterization of the changes in supine blood pressure with long-term use of droxidopa in patients with neurogenic orthostatic hypotension.

BACKGROUND AND AIMS: Patients with neurogenic orthostatic hypotension (nOH) due to autonomic dysfunction may also experience supine hypertension (defined as supine systolic blood pressure [SBP] ≥140 mmHg). Because pressor agents used to improve nOH symptoms by increasing standing blood pressure (BP) may exacerbate or cause supine hypertension, changes in supine BP with nOH treatments are of interest. METHODS: This post hoc study examined changes in SBP in patients receiving droxidopa (100-600 mg, three times daily) during a 12-month long-term extension study based on whether patients had supine hypertension (ie, supine SBP ≥140 mmHg) at baseline. Shifts from baseline in supine hypertension categorization and mean supine and standing SBP after 6 and 12 months of treatment with droxidopa were determined. RESULTS: At baseline, 64 patients did not have supine hypertension (mean supine SBP, 120 mmHg) and 38 patients had supine hypertension (mean supine SBP, 157 mmHg). A similar percentage of patients shifted from their respective baseline supine hypertension categorization (ie, with or without supine hypertension) to the other category after receiving droxidopa for 6 or 12 months. After 12 months of droxidopa treatment, patients with supine hypertension at baseline had a mean supine SBP decrease of 3 mmHg and a mean standing SBP increase of 9 mmHg. Patients without supine hypertension at baseline had mean supine and standing SBP increases of 12 and 15 mmHg, respectively. CONCLUSIONS: There was no consistent or progressive elevation in supine SBP over time during the 12-month treatment with droxidopa in patients either with or without supine hypertension at baseline. These data suggest that long-term droxidopa treatment for nOH does not adversely affect supine BP.

A Call to Action: The Role of Healthcare Providers in Reducing the Burden Associated with Neurogenic Orthostatic Hypotension.

Neurogenic orthostatic hypotension (nOH) is a sustained fall in blood pressure upon standing that frequently affects patients with neurodegenerative diseases (e.g., Parkinson disease) and manifests with symptoms such as lightheadedness and dizziness upon standing. nOH can severely affect patients by increasing the risk of falls and injuries and by decreasing functionality, independence, and quality of life. However, the condition is often under-recognized because of many factors, including the nonspecific nature of the symptoms, patient comorbidities, and patients' reluctance to discuss their symptoms with their healthcare providers. Increased awareness of the burden of nOH and recognition of potential barriers to efficient diagnosis may lead to improved clinical outcomes and better quality of life for patients. To better understand the manifestations and real-life impact of living with nOH symptoms, perspectives from a patient with nOH and his caregiver (wife) are provided, along with key findings from a published survey of patients and caregivers on the burden of nOH. In addition, insights and advice on a practical approach for diagnosing, educating, and treating patients with nOH are outlined.

This article discusses what neurogenic orthostatic hypotension (nOH) is, its symptoms, and how patients and healthcare providers (HCPs) can work together to manage nOH symptoms. What is nOH? People with neurologic disorders, like Parkinson disease, may also have a separate condition called nOH. nOH occurs when blood pressure drops too much when standing up after sitting or lying down. What are the symptoms of nOH, and how can they affect people's lives? Most often, people with nOH report feeling lightheaded, faint, or dizzy when standing up. Other symptoms of nOH include pain in the shoulders and neck, trouble thinking clearly, tiredness, or blurry vision. The symptoms of nOH can cause falls and injuries. Because of nOH symptoms, people may be unable to do daily activities and may feel worried or anxious. What do patients and HCPs need to know when discussing nOH symptoms? A survey showed that patients may not talk about their nOH symptoms with their HCPs unless symptoms are severe, and that patients can find receiving a diagnosis of nOH challenging. Patients can track nOH symptoms in a daily journal to use in discussions with their HCPs. How can HCPs help patients with nOH? HCPs can ask patients with underlying neurologic disorders about symptoms that occur on standing and confirm a diagnosis of nOH by comparing the patient's blood pressures measured lying down and after standing up. HCPs can provide information about lifestyle changes and medications that are available to manage nOH symptoms.

Characterization of the symptoms of neurogenic orthostatic hypotension and their impact from a survey of patients and caregivers.

BACKGROUND: Neurogenic orthostatic hypotension (nOH) results from impaired vasoconstriction due to dysfunction of the autonomic nervous system and is commonly associated with Parkinson disease (PD), multiple system atrophy (MSA), and pure autonomic failure. nOH can increase the risk of falls due to symptoms that include postural lightheadedness or dizziness, presyncope, and syncope. The purpose of this study was to obtain information from patients and caregivers regarding the symptoms and burden of nOH to expand on limited knowledge regarding the impact of nOH on quality of life. METHODS: This author-designed survey included questions regarding nOH (e.g., frequency and impact of symptoms, management) and was conducted online by Harris Poll via distribution to individuals who agreed to participate in Harris Poll online surveys or who were members of relevant disease advocacy organizations. Eligible patients were aged ≥ 18 years with PD, MSA, or pure autonomic failure and ≥ 1 of the following: orthostatic hypotension (OH), nOH, low blood pressure upon standing, or OH/nOH symptoms. Eligible caregivers cared for such patients but were not necessarily linked to any patient participant. RESULTS: Survey responses were received from 363 patients and 128 caregivers. PD was the most frequent underlying disorder (90% of patients; 88% of individuals managed by the caregivers). Despite meeting survey diagnosis criteria, a formal diagnosis of OH or nOH was reported by only 36% of patients and 16% of caregivers. The most frequent symptoms of nOH were dizziness or lightheadedness, fatigue when standing, and difficulty walking. A negative impact on patient quality of life caused by nOH symptoms was reported by 59% of patients and 75% of caregivers. Most respondents (≥87%) reported that nOH symptoms adversely affected patients' ability to perform everyday activities (most frequently physical activity/exercise, housework, and traveling). Falls (≥1) in the previous year due to nOH symptoms were reported by 57% of patients and 80% of caregivers. CONCLUSIONS: These survey results support the premise that nOH symptoms have a substantial negative impact on patient function and quality of life. The relatively low rates of formal nOH/OH diagnosis suggest the need for heightened awareness regarding the condition and its symptom burden.

Comparison of the Pharmacokinetics of Droxidopa After Dosing in the Fed Versus Fasted State and with 3-Times-Daily Dosing in Healthy Elderly Subjects.

BACKGROUND: Droxidopa is an oral prodrug of norepinephrine approved for the treatment of symptomatic neurogenic orthostatic hypotension. This two-part, randomized, crossover study evaluated the 24-h pharmacokinetic profile of droxidopa in 24 healthy elderly subjects. METHODS: Noncompartmental analysis was used to calculate the area under the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax), time of Cmax (tmax), and elimination half-life (t½e) of droxidopa and metabolites. Droxidopa was administered in the fed (high-fat/high-calorie meal) or fasted state either as a single 300-mg dose (three 100-mg capsules) or 3 times/day (TID) (three 100-mg capsules) at 4-h intervals. RESULTS: Administration of a single droxidopa dose in the fed versus fasted state decreased mean Cmax (2057 vs 3160 ng/mL) and mean AUC (10,927 vs 13,857 h × ng/mL) and increased median tmax twofold (4.00 vs 2.00 h). Differences between the fed and fasted state for mean t½e (2.58 vs 2.68 h) were not observed. Fed versus fasted geometric mean ratios for Cmax and AUC were 66% [90% confidence interval (CI) 60.7-71.7] and 80% (90% CI 72.6-88.1), respectively. With TID dosing, similar values for Cmax were observed after each dose (range 2789-3389 ng/mL) with no return to baseline between doses. Norepinephrine Cmax was 895 pg/mL following dose 1, with no further increases upon subsequent doses; norepinephrine levels remained above baseline for 12-16 h after dose 1. CONCLUSIONS: Absorption of a single dose of droxidopa is slowed after a high-fat/high-calorie meal; for consistent effect, administer droxidopa in the same manner (with or without food). Pharmacokinetic parameters of droxidopa are similar after single and TID dosing. ClinicalTrials.gov Identifier: NCT01149629.

Integrated Analysis of Droxidopa for the Treatment of Neurogenic Orthostatic Hypotension in Patients with Parkinson Disease.

INTRODUCTION: Neurogenic orthostatic hypotension (nOH) is associated with neurodegenerative conditions, may cause symptoms of end-organ hypoperfusion, increases fall risk, and can negatively impact quality of life. Droxidopa is approved for the treatment of symptomatic nOH in adults. As the largest subpopulation of patients with nOH has a diagnosis of Parkinson disease (PD), the efficacy and tolerability of droxidopa in patients with PD and nOH were examined using integrated clinical trial data. METHODS: Post hoc analyses included data from the phase 3, randomized, placebo-controlled clinical trials of droxidopa (two short-term [1-2 weeks] trials and one medium-term [8-10 weeks] trial) in the subset of participants with PD and symptomatic nOH. Efficacy was assessed using standing blood pressure (BP) measurements and the Orthostatic Hypotension Questionnaire (OHQ), a patient-reported evaluation of nOH symptoms (Orthostatic Hypotension Symptom Assessment [OHSA]), and their impact (Orthostatic Hypotension Daily Activity Scale [OHDAS]). RESULTS: The analysis included 307 patients with PD (droxidopa, n = 150; placebo, n = 157). Compared with placebo, droxidopa significantly improved the OHQ composite score (P = 0.014), the OHSA composite score (P = 0.022), and the OHDAS composite score (P = 0.029) from baseline to end of study/week one. We found significant increases in standing mean systolic/diastolic BP for droxidopa versus placebo (P = 0.003/0.002). Adverse event (AE) rates were qualitatively similar between groups; the most frequently reported AEs in the droxidopa groups included headache, dizziness, nausea, and hypertension. CONCLUSIONS: These post hoc analyses suggest that droxidopa provides meaningful clinical benefits and is well tolerated in the treatment of symptomatic nOH in patients with PD.

Impact of the Norepinephrine Prodrug Droxidopa on the QTc Interval in Healthy Individuals.

A double-blind, 4-period crossover study (NCT01327066) was conducted to assess the effect of the novel norepinephrine prodrug droxidopa on the QT interval in in healthy subjects. Subjects were randomized to receive a single dose of droxidopa 600 mg (maximal dose) and 2000 mg (supratherapeutic dose) compared with the positive control, moxifloxacin 400 mg, and placebo, each separated by a 3-day washout period. Patients were monitored by continuous Holter monitoring, and electrocardiograms (ECGs) were extracted 0.5-23 hours after dosing. Blood samples for pharmacokinetic analysis were collected before dosing and after ECG data collection. The primary end point was the time-matched placebo-adjusted change from baseline in the individually corrected QT (QTcI). The time-averaged QTcI mean placebo-corrected changes from baseline for droxidopa 600 and 2000 mg were 0.1 milliseconds (90%CI, -0.9 to 1.0 milliseconds) and 0.3 milliseconds (90%CI, -0.6 to 1.3 milliseconds), respectively, and 9 milliseconds (90%CI, 8.4-10.3 milliseconds) for moxifloxacin. This study found no effect of either dose of droxidopa on cardiac repolarization using QTcI. Analysis of the pharmacokinetic/pharmacodynamic relationship and cardiac repolarization showed no association with droxidopa exposure. There were no clinically relevant effects of droxidopa on heart rate, atrioventricular conduction, or cardiac depolarization identified. No morphologic ECG changes were observed.

Cardiovascular Safety of Droxidopa in Patients With Symptomatic Neurogenic Orthostatic Hypotension.

The norepinephrine prodrug droxidopa improves symptoms of neurogenic orthostatic hypotension, a condition that is associated with diseases of neurogenic autonomic failure (e.g., Parkinson disease, multiple system atrophy, pure autonomic failure). These conditions are more prevalent in older patients who also have cardiovascular co-morbidities. Hence, we evaluated the cardiovascular safety of droxidopa in patients with symptomatic neurogenic orthostatic hypotension who participated in randomized controlled studies (short-term studies of 1 to 2 weeks and an intermediate 8- to 10-week study) and long-term open-label studies. Rates of cardiovascular adverse events (AEs) for patients treated with droxidopa were 4.4% in the intermediate study and 10.8% in the long-term open-label studies. Adjusting for exposure time, cardiovascular AE rates were 0.30 events/patient-year in the short-term and intermediate studies and 0.15 events/patient-year in the long-term open-label studies. The incidence of treatment discontinuation due to blood pressure-related events was approximately 2.5%. Among patients with a history of cardiac disorders at baseline, the rates of cardiovascular-related and blood pressure-related AEs were nominally higher with droxidopa compared to placebo. Most of these events were minor atrial arrhythmias; none were major adverse cardiovascular events or deaths. In conclusion, small increases in cardiovascular AEs were observed with droxidopa compared to placebo; this was most evident in patients with preexisting cardiac disorders.

Effects of the novel norepinephrine prodrug, droxidopa, on ambulatory blood pressure in patients with neurogenic orthostatic hypotension.

The prodrug droxidopa increases blood pressure (BP) in patients with neurogenic orthostatic hypotension. The BP profile of droxidopa in neurogenic orthostatic hypotension patients (n = 18) was investigated using ambulatory BP monitoring. Following dose optimization and a washout period, 24-hour "off-drug" data were collected. "On-drug" assessment was conducted after 4-5 weeks of droxidopa treatment (mean dose, 444 mg, three times daily). Ambulatory monitoring off drug revealed that 90% of patients already had abnormalities in the circadian BP profile and did not meet criteria for normal nocturnal BP dipping. On treatment, both overall mean 24-hour systolic and diastolic BPs were higher compared to off drug (137/81 mm Hg vs. 129/76 mm Hg; P = .017/.002). Mean daytime systolic BP was significantly higher with droxidopa (8.4 ± 3.1 mm Hg; P = .014). Although nocturnal BP was not significantly higher on droxidopa versus off treatment (P = .122), increases in nocturnal (supine) BP ≥10 mm Hg were observed in four cases (22%). Severe supine systolic hypertensive readings at night (>200 mm Hg) were captured in one case and only while on treatment. These data demonstrate that ambulatory BP monitoring is useful to evaluate the circadian BP profile after initiating treatment with a pressor agent.

Analysis of number needed to treat for droxidopa in patients with symptomatic neurogenic orthostatic hypotension.

BACKGROUND: Droxidopa is an orally active prodrug that significantly improved dizziness/lightheadedness measured using the Orthostatic Hypotension Symptom Assessment (OHSA) Item 1 in patients with neurogenic orthostatic hypotension (nOH) caused by primary autonomic failure (Parkinson disease, multiple system atrophy, and pure autonomic failure), dopamine ß-hydroxylase deficiency, or nondiabetic autonomic neuropathy. The efficacy and safety of droxidopa were assessed by determining the number needed to treat (NNT) and the number needed to harm (NNH). METHODS: Data collected in randomized, placebo-controlled clinical studies in adults with a clinical diagnosis of symptomatic nOH were pooled for efficacy and safety analyses. NNT and NNH were calculated as reciprocals of the risk difference (difference in event rates) for droxidopa versus placebo. RESULTS: The NNT for droxidopa for improvement in OHSA Item 1 was <10. The NNH for adverse events (AEs) leading to discontinuation in the pooled studies was 81. The likelihood of being helped or harmed (LHH) calculated from pooled analysis of the NNT for ≥2 units of improvement in OHSA Item 1 score and the NNH for discontinuations due to AEs were 7.8, 8.8, 3.1, and 3.5 for weeks 1, 2, 4, and 8 after randomization, respectively. CONCLUSIONS: Droxidopa is efficacious for treatment of nOH, with an NNT below 10 and an acceptable tolerability profile with NNH ranging from 23 to 302 in the pooled analysis of frequently occurring AEs. Based on the LHH for the pooled analysis at week 1, droxidopa is 7.8 times more likely than placebo to show a clinical benefit than result in discontinuation because of an AE. TRIAL REGISTRATIONS: ClinicalTrials.gov identifiers: NCT00782340 , first received October 29, 2008; NCT00633880 , first received March 5, 2008; and NCT01176240 , first received July 30, 2010.

Droxidopa and Reduced Falls in a Trial of Parkinson Disease Patients With Neurogenic Orthostatic Hypotension.

OBJECTIVES: Droxidopa is a prodrug of norepinephrine indicated for the treatment of orthostatic dizziness, lightheadedness, or the "feeling that you are about to black out" in adult patients with symptomatic neurogenic orthostatic hypotension caused by primary autonomic failure including Parkinson disease (PD). The objective of this study was to compare fall rates in PD patients with symptomatic neurogenic orthostatic hypotension randomized to droxidopa or placebo. METHODS: Study NOH306 was a 10-week, phase 3, randomized, placebo-controlled, double-blind trial of droxidopa in PD patients with symptomatic neurogenic orthostatic hypotension that included assessments of falls as a key secondary end point. In this report, the principal analysis consisted of a comparison of the rate of patient-reported falls from randomization to end of study in droxidopa versus placebo groups. RESULTS: A total of 225 patients were randomized; 222 patients were included in the safety analyses, and 197 patients provided efficacy data and were included in the falls analyses. The 92 droxidopa patients reported 308 falls, and the 105 placebo patients reported 908 falls. In the droxidopa group, the fall rate was 0.4 falls per patient-week; in the placebo group, the rate was 1.05 falls per patient-week (prespecified Wilcoxon rank sum P = 0.704; post hoc Poisson-inverse Gaussian test P = 0.014), yielding a relative risk reduction of 77% using the Poisson-inverse Gaussian model. Fall-related injuries occurred in 16.7% of droxidopa-treated patients and 26.9% of placebo-treated patients. CONCLUSIONS: Treatment with droxidopa appears to reduce falls in PD patients with symptomatic neurogenic orthostatic hypotension, but this finding must be confirmed.

Cost-effectiveness of droxidopa in patients with neurogenic orthostatic hypotension: post-hoc economic analysis of Phase 3 clinical trial data.

OBJECTIVE: Falls are associated with neurogenic orthostatic hypotension (nOH) and are an economic burden on the US healthcare system. Droxidopa is approved by the US FDA to treat symptomatic nOH. This study estimates the cost-effectiveness of droxidopa vs standard of care from a US payer perspective. METHODS: A Markov model was used to predict numbers of falls and treatment responses using data from a randomized, double-blind trial of patients with Parkinson's disease and nOH who received optimized droxidopa therapy or placebo for 8 weeks. The severity of falls, utility values, and injury-related costs were derived from published studies. Model outcomes included number of falls, number of quality-adjusted life-years (QALYs), and direct costs. Incremental cost-effectiveness ratios (ICERs) were calculated. Outcomes were extrapolated over 12 months. RESULTS: Patients receiving droxidopa had fewer falls compared with those receiving standard of care and gained 0.33 QALYs/patient. Estimated droxidopa costs were $30,112, with estimated cost savings resulting from fall avoidance of $14,574 over 12 months. Droxidopa was cost-effective vs standard of care, with ICERs of $47,001/QALY gained, $24,866 per avoided fall with moderate/major injury, and $1559 per avoided fall with no/minor injury. The main drivers were fall probabilities and fear of fall-related inputs. LIMITATIONS: A limitation of the current study is the reliance on falls data from a randomized controlled trial where the placebo group served as the proxy for standard of care. Data from a larger patient population, reflecting 'real-life' patient use and/or comparison with other agents used to treat nOH, would have been a useful complement, but these data were not available. CONCLUSION: Using Markov modeling, droxidopa appears to be a cost-effective option compared with standard of care in US clinical practice for the treatment of nOH.

A randomized, placebo-controlled, phase 2 study of the efficacy and safety of droxidopa in patients with intradialytic hypotension.

INTRODUCTION: Intradialytic hypotension (IDH) is the most common complication of hemodialysis (HD), and it plays a significant role in the morbidity and mortality associated with maintenance HD. METHODS: This was a placebo-controlled, parallel-group study evaluating efficacy and safety of droxidopa in improving intradialytic blood pressure (BP) responses in 85 adults with end-stage renal disease (ESRD) and prone to IDH. Following screening and baseline periods, patients received 400 mg or 600 mg droxidopa, or placebo, orally 1 hour before HD for 4 weeks. Primary outcome endpoint was the change between baseline and last 2 treatment weeks in average mean arterial pressure (MAP) during HD. Also assessed were changes from baseline in systolic BP (SBP) and diastolic BP (DBP) during and after HD; number of hypotension-induced interventions and symptoms; and adverse events. RESULTS: Increase in droxidopa intra-HD MAP were not significantly different from placebo, although droxidopa groups showed significant improvements in mean SBP after HD of +4.8 ± 11.6 mm Hg (600-mg) and +3.4 ± 13.1 (400-mg) compared with -4.4 ± 17.9 mm Hg in placebo, and the drop seen in mean nadir SBP pre- to intra-HD was also reduced. Changes in mean DBP pre- and post-HD, changes in mean nadir SBP post-HD, or intra-HD SBP were not significant over the treatment period. HD terminations decreased 5-fold in the 600-mg group and 2-fold in the 400-mg group, whereas the number of discontinuations stayed unchanged in the placebo group. Overall, treatment with 600-mg or 400-mg droxidopa was well tolerated in this population. CONCLUSION: These data suggest that droxidopa may have a role in reducing IDH complications in patients with ESRD on chronic HD.

Droxidopa for the short-term treatment of symptomatic neurogenic orthostatic hypotension in Parkinson's disease (nOH306B).

Neurogenic orthostatic hypotension (nOH) results from failure of norepinephrine responses to postural change to maintain standing systolic blood pressure (s-SBP). Droxidopa is an oral prodrug of norepinephrine. Study nOH306 enrolled patients with Parkinson's disease (PD) and symptomatic nOH. Subjects underwent up to 2 weeks of double-blind titration of droxidopa or placebo, followed by 8 weeks of double-blind maintenance treatment (100-600 mg thrice-daily). For the initial 51 subjects (study nOH306A, previously reported), the primary efficacy measure, Orthostatic Hypotension Questionnaire (OHQ) composite score, did not demonstrate significant change versus placebo at maintenance week 8. For the subsequent 171 subjects (study nOH306B, reported here), the primary efficacy measure was change versus placebo on item 1 ("dizziness, lightheadedness, feeling faint, or feeling like you might black out") of the Orthostatic Hypotension Symptom Assessment (OHSA) subsection of the OHQ at maintenance week 1. At week 1, mean (standard deviation) improvement on OHSA item 1 was 2.3 (2.95) for droxidopa versus 1.3 (3.16) for placebo (P = 0.018). In addition, mean increase in s-SBP at week 1 was 6.4 (18.85) for droxidopa versus 0.7 (20.18) mmHg for placebo (nominal P value: 0.032). Differences in change in OHSA item 1 scores from baseline to maintenance weeks 2, 4, and 8 were not statistically significant. Adverse-event (AE) incidence was similar across groups, but 12.4% of droxidopa and 6.1% of placebo subjects withdrew because of AEs. The most common AEs on droxidopa (vs. placebo) were headache (13.5% vs. 7.3%) and dizziness (10.1% vs. 4.9%). Study nOH306B demonstrated subjective (OHSA item 1) and objective (s-SBP) evidence of short-term droxidopa efficacy (vs. placebo) for symptomatic nOH in PD.

Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa.

UNLABELLED: We evaluated whether droxidopa, a prodrug converted to norepinephrine, is beneficial in the treatment of symptomatic neurogenic orthostatic hypotension, which results from failure to generate an appropriate norepinephrine response to postural challenge. Patients with symptomatic neurogenic orthostatic hypotension and Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa titration (100-600 mg, 3× daily). Responders then received an additional 7-day open-label treatment at their individualized dose. Patients were subsequently randomized to continue with droxidopa or withdraw to placebo for 14 days. We then assessed patient-reported scores on the Orthostatic Hypotension Questionnaire and blood pressure measurements. Mean worsening of Orthostatic Hypotension Questionnaire dizziness/lightheadedness score from randomization to end of study (the primary outcome; N=101) was 1.9±3.2 with placebo and 1.3±2.8 units with droxidopa (P=0.509). Four of the other 5 Orthostatic Hypotension Questionnaire symptom scores and all 4 symptom-impact scores favored droxidopa, with statistical significance for the patient's self-reported ability to perform activities requiring standing a short time (P=0.033) and standing a long time (P=0.028). Furthermore, a post hoc analysis of a predefined composite score of all symptoms (Orthostatic Hypotension Questionnaire composite) demonstrated a significant benefit for droxidopa (P=0.013). There was no significant difference between groups for standing systolic blood pressure (P=0.680). Droxidopa was well tolerated. In summary, this randomized withdrawal droxidopa study failed to meet its primary efficacy end point. Additional clinical trials are needed to confirm that droxidopa is beneficial in symptomatic neurogenic orthostatic hypotension, as suggested by the positive secondary outcomes of this trial. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00633880.

Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial.

OBJECTIVE: To determine whether droxidopa, an oral norepinephrine precursor, improves symptomatic neurogenic orthostatic hypotension (nOH). METHODS: Patients with symptomatic nOH due to Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa dose optimization (100-600 mg 3 times daily), followed, in responders, by 7-day washout and then a 7-day double-blind trial of droxidopa vs placebo. Outcome measures included patient self-ratings on the Orthostatic Hypotension Questionnaire (OHQ), a validated, nOH-specific tool that assesses symptom severity and symptom impact on daily activities. RESULTS: From randomization to endpoint (n = 162), improvement in mean OHQ composite score favored droxidopa over placebo by 0.90 units (p = 0.003). Improvement in OHQ symptom subscore favored droxidopa by 0.73 units (p = 0.010), with maximum change in "dizziness/lightheadedness." Improvement in symptom-impact subscore favored droxidopa by 1.06 units (p = 0.003), with maximum change for "standing a long time." Mean standing systolic blood pressure (BP) increased by 11.2 vs 3.9 mm Hg (p < 0.001), and mean supine systolic BP by 7.6 vs 0.8 mm Hg (p < 0.001). At endpoint, supine systolic BP >180 mm Hg was observed in 4.9% of droxidopa and 2.5% of placebo recipients. Adverse events reported in ≥ 3% of double-blind droxidopa recipients were headache (7.4%) and dizziness (3.7%). No patients discontinued double-blind treatment because of adverse events. CONCLUSIONS: In patients with symptomatic nOH, droxidopa improved symptoms and symptom impact on daily activities, with an associated increase in standing systolic BP, and was generally well tolerated. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with symptomatic nOH who respond to open-label droxidopa, droxidopa improves subjective and objective manifestation of nOH at 7 days.

Droxidopa in patients with neurogenic orthostatic hypotension associated with Parkinson's disease (NOH306A).

BACKGROUND: Neurogenic orthostatic hypotension (nOH) is common in Parkinson's disease (PD), and represents a failure to generate norepinephrine responses appropriate for postural change. Droxidopa (L-threo-3,4-dihydroxyphenylserine) is an oral norepinephrine prodrug. OBJECTIVE: Interim analyses of the initial patients enrolled in a multicenter, randomized, double-blind, placebo-controlled phase 3 trial of droxidopa for nOH in PD (ClinicalTrials.gov Identifier: NCT01176240). METHODS: PD patients with documented nOH underwent ≤ 2 weeks of double-blind droxidopa or placebo dosage optimization followed by 8 weeks of maintenance treatment (100-600 mg t.i.d.). The primary efficacy measure was change in Orthostatic Hypotension Questionnaire (OHQ) composite score from baseline to Week 8. Key secondary variables included dizziness/lightheadedness score (OHQ item 1) and patient-reported falls. RESULTS: Among 24 droxidopa and 27 placebo recipients, mean OHQ composite-score change at Week 8 was -2.2 versus -2.1 (p = 0.98); in response to this pre-planned futility analysis, the study was temporarily stopped and all data from these patients were considered exploratory. At Week 1, mean dizziness/lightheadedness score change favored droxidopa by 1.5 units (p = 0.24), with subsequent numerical differences favoring droxidopa throughout the observation period, and at Week 1, mean standing systolic blood-pressure change favored droxidopa by 12.5 mmHg (p = 0.04). Compared with placebo, the droxidopa group exhibited an approximately 50% lower rate of reported falls (p = 0.16) and fall-related injuries (post-hoc analysis). CONCLUSIONS: This exploratory analysis of a small dataset failed to show benefit of droxidopa, as compared with placebo by the primary endpoint. Nonetheless, there were signals of potential benefit for nOH, including improvement in dizziness/lightheadedness and reduction in falls, meriting evaluation in further trials.

Efficacy and safety of CH-1504, a metabolically stable antifolate, in patients with active rheumatoid arthritis: results of a phase II multicenter randomized study.

OBJECTIVE: To investigate the potential efficacy, safety, and tolerability of daily use of CH-1504 in patients with active rheumatoid arthritis (RA). US National Institutes of Health database no. NCT00658047. METHODS: In our phase II randomized double-blind double-dummy study, patients naive to methotrexate (MTX; n = 201) and having moderate to severe RA received either CH-1504 (0.25 mg, 0.5 mg, or 1.0 mg once-daily oral doses) or MTX (titrated to 20.0 mg once-weekly oral doses). All received weekly 10-mg folate supplementation. Efficacy and safety were assessed at 2, 4, 8, and 12 weeks, with a treatment-free followup at 16 weeks. Safety and tolerability were assessed. Primary efficacy endpoint was proportion of patients achieving ACR20 response at Week 12. Secondary endpoints included difference from baseline in the 28-joint Disease Activity Score (DAS28) and individual components of the American College of Rheumatology (ACR) composite index. RESULTS: Demographic characteristics were similar in all treatment groups: mean age 54.3 ± 11.4 years, female sex 87%, mean baseline DAS28 6.6 ± 0.9. At Week 12, CH-1504 demonstrated comparable efficacy compared to MTX as measured by ACR20, DAS28, and ACR composite core-set measures, including tender and swollen joints. No dose-response relationship was observed. Adverse events across treatment groups were mild. Liver enzyme levels increased from baseline to Week 16 in the MTX group, with qualitatively lesser increases in the CH-1504 groups. Two patients in the MTX group withdrew because of gastrointestinal-related adverse events. CH-1504 appeared safe and well tolerated at all dose levels. CONCLUSION: CH-1504 has comparable efficacy to MTX and is safe and well tolerated. Metabolically stable antifolates are a promising therapeutic option that warrants further study.