Fixed-Dose Combination of Dapagliflozin + Sitagliptin + Metformin in Patients with Type 2 Diabetes Poorly Controlled with Metformin: Phase 3, Randomized Comparison with Dual Combinations.

INTRODUCTION: This study compared efficacy and safety of triple drug fixed-dose combination (FDC) of dapagliflozin (DAPA) + sitagliptin (SITA) + metformin (MET) extended release (ER) with SITA + MET sustained release (SR) and DAPA + MET ER in patients with type 2 diabetes poorly controlled with metformin. METHODS: This phase 3, randomized, open-label, active-controlled study included adult patients with glycated hemoglobin (HbA1c) ≥ 8% (64 mmol/mol) and ≤ 11% (97 mmol/mol), randomized in 1:1:1 ratio to receive either FDC of DAPA + SITA + MET ER (10 mg + 100 mg + 1000 mg) tablets once daily (n = 137) or co-administration of SITA + MET SR (100 mg + 1000 mg) tablets once daily (n = 139) or FDC of DAPA + MET ER (10 mg + 1000 mg) tablets once daily (n = 139). Primary endpoint was mean change in HbA1c from baseline to week 16. RESULTS: Mean baseline HbA1c was approximately 9% (75 mmol/mol) in each treatment group. At week 16, adjusted mean reduction in HbA1c from baseline was significantly greater with DAPA + SITA + MET ER (- 1.73% [- 19.0 mmol/mol]) compared to SITA + MET SR (- 1.28% [- 14.1 mmol/mol]; difference of - 0.46% [- 5.1 mmol/mol], p < 0.001) and DAPA + MET ER (- 1.33% [- 14.6 mmol/mol]; difference - 0.4% [4.4 mmol/mol], p < 0.001). Similarly, at week 12, reduction in HbA1c from baseline was significantly greater with DAPA + SITA + MET ER compared to SITA + MET SR (p = 0.0006) and DAPA + MET ER (p = 0.0276). At week 16, DAPA + SITA + MET ER showed significant reduction in postprandial blood glucose compared to DAPA + MET ER (p = 0.0394) and significant reduction in fasting blood glucose with DAPA + SITA + MET ER compared to SITA + MET SR (p = 0.0226). The proportion of patients achieving HbA1c < 7.0% (53 mmol/mol) at week 16 was significantly higher with DAPA + SITA + MET ER (38.5%) versus SITA + MET SR (12.8%) (p < 0.001) and DAPA + MET ER (21.3%) (p = 0.0023). All study medications were well tolerated. CONCLUSION: Triple FDC of DAPA + SITA + MET ER tablets once daily was significantly better in achieving glycemic control versus dual combination once daily in patients with type 2 diabetes poorly controlled with metformin without any significant safety concerns. TRIAL REGISTRATION: CTRI/2021/11/038176, registered on 22 November 2021.

Type 2 diabetes is a progressive disease in which the risks of microvascular and macrovascular complications and mortality are strongly associated with hyperglycemia. Achieving glycemic control remains the main goal of treatment to prevent these complications. Estimates in 2019 showed that 77 million individuals had diabetes in India, which is expected to rise over 134 million by 2045. Considering the progressive nature of the disease, many guidelines recommend use of dual or triple drug therapy based on glycated hemoglobin (HbA1c) level. Use of fixed-dose combination (FDC) helps to improve therapy compliance and can provide optimum therapeutic benefits. Mechanisms of action of dipeptidyl peptidase 4 (DPP4) and sodium­glucose cotransporter 2 (SGLT2) inhibitors are complementary to that of metformin with low risk of hypoglycemia. Studies have shown beneficial effects of adding both DPP4 inhibitors and SGLT2 inhibitors after metformin monotherapy. This phase 3 study was designed to assess efficacy and safety of triple FDC of dapagliflozin + sitagliptin + metformin extended release in comparison with combipack of sitagliptin + metformin sustained release and FDC of dapagliflozin + metformin ER in patients with type 2 diabetes inadequately controlled with metformin monotherapy. The study demonstrated superiority of triple FDC of dapagliflozin + sitagliptin + metformin ER over dual combinations in terms of reduction in HbA1c and percentage of patients achieving target HbA1c at the end of week 16. The current study provides evidence for considering triple FDC of dapagliflozin + sitagliptin + metformin ER as an alternative option with minimal risk of hypoglycemia and weight gain, while considering oral triple-combination therapy for patients to achieve their glycemic target.

Efficacy and Safety of Pregabalin Prolonged Release-Etoricoxib Combination Compared to Etoricoxib for Chronic Low Back Pain: Phase 3, Randomized Study.

INTRODUCTION: Currently available treatments for chronic lower back pain (CLBP) do not adequately address both nociceptive and neuropathic components of pain. We evaluated efficacy and safety of fixed-dose combination (FDC) of low-dose pregabalin prolonged release 75 mg-etoricoxib 60 mg to address both pain components. METHODS: This randomized phase 3 trial conducted at 12 centres across India evaluated efficacy (based on mean change in numeric rating scale [NRS], Roland-Morris disability questionnaire [RDQ], visual analogue scale [VAS], patient global impression of improvement [PGI-I], clinical global impression of improvement [CGI-I] and rescue medication consumption) and safety of FDC in comparison to etoricoxib alone in adult patients with CLBP. Treatment duration was 8 weeks. RESULTS: Of the 371 patients screened, 319 were randomized and considered for efficacy and safety analysis. Both treatment groups had no significant difference in terms of demography and baseline disease characteristics. Significantly better outcomes with FDC compared to etoricoxib were observed at week 4 onwards. At week 8, both groups showed significant reduction in mean NRS score from baseline (- 4.00 ± 1.65 in FDC; - 2.92 ± 1.59 in etoricoxib) with mean NRS score being significantly less in the FDC group compared to etoricoxib group (3.26 ± 1.56 vs 4.31 ± 1.56; p < 0.0001). The FDC was more effective than etoricoxib in terms of significantly greater reduction in RDQ score (- 9.28 ± 4.48 vs - 6.78 ± 4.34; p < 0.0001) and VAS score (- 37.66 ± 18.7 vs - 28.50 ± 16.31; p < 0.0001) at week 8. The FDC was also better in terms of significantly more patients reporting their condition as 'very much better' (36.9% vs 5.0%; p < 0.0001) and clinicians reporting patient's condition as 'very much improved' (36.3% vs 5.7%; p < 0.0001). Overall, study medications were well tolerated. CONCLUSION: FDC of pregabalin and etoricoxib provided significant benefits in reducing pain and improving functional status compared with etoricoxib alone in patients with CLBP. Pregabalin prolonged release-etoricoxib FDC could be one of the treatment options for early and sustained pain relief and improvement in quality-of-life in treating CLBP as it addresses both neuropathic and nociceptive components of pain. TRIAL REGISTRATION: CTRI/2018/10/015886.

Low back pain is one of the most common causes of loss of productivity worldwide. About 60% of Indians suffer from low back pain at some point. Low back pain that persists for more than 3 months is classified as chronic low back pain which mostly includes both nociceptive and neuropathic components. Monotherapies, if prescribed, are not completely effective, as they generally only target either nociceptive or neuropathic components of pain. Multiple drugs are usually needed at multiple times a day, at higher doses for optimal effectiveness, and in most cases they have significant side effects if taken over prolonged periods and also add to the pill burden. To minimize treatment-associated adverse effects, and to increase treatment compliance, while addressing both the components of pain, we developed a fixed-dose combination of low-dose pregabalin prolonged release and etoricoxib. A phase 3 trial was designed to assess the efficacy and safety of the fixed-dose combination in comparison with etoricoxib alone in treating chronic low back pain. The combination demonstrated statistically and clinically significant improvement in patient-reported outcomes­pain, functionality and quality of life­as early as 4 weeks after starting the medication. No severe or serious adverse effects were reported. Thus, the combination of low-dose pregabalin prolonged release and etoricoxib could provide an option for optimal management of chronic low back pain. This would provide multiple benefits, such as addressing both nociceptive and neuropathic components of chronic low back pain, reducing drug-related adverse effects because of low dose, reducing pill burden and thereby increasing drug compliance.

A Real-World, Non-interventional Indian Study Evaluating Intensive Plant-Based Butter Moisturizing Cream in Psoriasis.

INTRODUCTION: Psoriasis is estimated to affect 0.44-2.8% of the Indian population. Moisturizers are a key adjuvant psoriasis treatment strategy, but data regarding their effectiveness, safety and compliance pattern in an Indian context are lacking. Hence, this real-world study on an intensive plant-based butter moisturizing cream (Venusia ® Max) was conducted among Indian patients with psoriasis. METHODS: This was an observational, patient-reported outcomes (PRO) study in patients with psoriasis aged 18-75 years who were prescribed the cream in routine clinical practice, as per clinician's discretion, over 4 weeks. The primary outcome measure was improvement from baseline in quality of life assessed using the Dermatology Quality of Life Index (DLQI) at 4 weeks of the study period. The secondary outcome measures were improvement in dryness using the Dry Skin/Ichthyosis Area and Severity Index (DASI) score at 4 weeks, safety and compliance. The DLQI and DASI scores were recorded by the clinicians at baseline and after 2 (optional) and 4 weeks of starting the cream. Safety was assessed throughout the study. RESULTS: The study included 400 patients from 9 outpatient dermatology centers across India. Of 400 patients, 384 completed the study. A significant reduction in both the mean DLQI score (66.7%; p < 0.001) and mean DASI score (84.6%; p < 0.001) was observed at week 4 after starting the cream vs. baseline in the overall population. Overall, the cream showed a good safety and compliance profile during the study period. There were no serious adverse events or deaths. CONCLUSIONS: The evidence from the PRO study suggests that use of the intensive plant-based butter moisturizing cream in a real-world scenario has a noticeable impact on improving the quality of life and reducing the skin dryness associated with psoriasis over 4 weeks. The moisturizing cream may serve as a valuable adjuvant treatment option for the management of psoriasis. TRIAL REGISTRATION NUMBER: CTRI/2017/03/008023. FUNDING: Dr. Reddy's Laboratories Ltd.

Real-World, Non-Interventional, Observational Study to Evaluate Effectiveness and Tolerability of Acotiamide Hydrochloride Hydrate in Treatment of Functional Dyspepsia.

INTRODUCTION: Functional dyspepsia (FD) is a highly prevalent condition which reduces patients' quality of life (QoL) and imparts a significant economic burden on the healthcare system. Acotiamide is a novel prokinetic agent useful in treatment of FD, and this study evaluated the effectiveness of acotiamide hydrochloride hydrate in management of FD over a 4-week period in a real-world setting. METHODS: This study was a prospective, observational, real-world data collection of 132 patients (85 male, 47 female) over 18 years of age diagnosed with FD as per Rome III criteria and treated with acotiamide for 4 weeks at a gastroenterology unit of a medical school in India. Those receiving prokinetics and cholinergic drugs, having any structural lesion on endoscopy, with coexisting irritable bowel syndrome and having heartburn in the past 12 weeks were excluded. Primary outcome was responders based on overall treatment efficacy (OTE) recorded on a seven-point Likert scale for postprandial distress syndrome (PDS; postprandial fullness, early satiety and upper abdominal bloating), epigastric pain syndrome (EPS; upper abdominal pain and upper abdominal discomfort) and associated symptoms (nausea, vomiting and excessive belching) at the end of 2 and 4 weeks. Secondary outcomes were elimination of symptoms of PDS, QoL assessed on the Short-Form Nepean Dyspepsia Index (SFNDI) questionnaire and clinical safety after 2 and 4 weeks. RESULTS: The responder rates with acotiamide at 2 and 4 weeks were 51.5% and 65.9%, respectively, for PDS. Similarly, the responder rates for EPS were 31.8% and 41.7%, respectively, at 2 weeks and 4 weeks. The responder rates for associated symptoms of nausea, vomiting and excessive belching were respectively 18.2%, 17.4% and 16.7% at 2 weeks and 18.2%, 17.4% and 18.2% at 4 weeks. Symptom elimination rates were 9.8% and 18.9% for postprandial fullness, 12.9% and 22.0% for early satiety, and 18.9% and 24.2% for abdominal bloating at 2 and 4 weeks, respectively. Significant improvement (p < 0.0001) in the SFNDI total scores from 25.91 (5.00) at 2 weeks to 23.76 (4.84) at 4 weeks were found at 4 weeks compared to 2 weeks. A total of 7 (5.30%) patients reported mild adverse events which were dizziness (4), headache (3) and nausea (1). CONCLUSION: The current study demonstrates that treatment with acotiamide improves symptoms, QoL and is well tolerated in Indian patients with FD. TRIAL REGISTRATION: Clinical Trial Registry of India, CTRI/2017/11/010421. FUNDING: Dr. Reddy's Laboratories, India.