Quantitative comparison of the efficacy of clinical drug treatments for primary progressive multiple sclerosis.

OBJECTIVE: This study proposes a comprehensive quantitative evaluation of the efficacy of drugs and placebo in clinical trials for primary progressive multiple sclerosis (PPMS). METHODS: A literature search was conducted using the PubMed, EMBASE, and Cochrane library databases and the clinical studies reporting drug efficacy in the treatment of PPMS were included in the analyses. The cumulative proportion of patients without confirmed disability progression (wCDP%) was used as the main efficacy endpoint. The model-based meta-analysis method was used to describe the time course of each drug (as well as placebo) in order to rank the drug efficacy for the treatment of PPMS. RESULTS: Fifteen studies involving 3779 patients were included, of which, nine were placebo-controlled and six were single-arm trials. Twelve drugs were included in the study. The results showed that, except for biotin, interferon ß-1a, and interferon ß-1b, whose efficacy was comparable to the placebo, the efficacy of the other 9 drugs were significantly better than placebo. Among these, ocrelizumab showed outstanding performance, with wCDP% of 72.6 at 96 weeks, while the proportions of rest of the drugs ranged between approximately 55-70%. CONCLUSION: The results of this study provide the necessary quantitative information for both the rational clinical use of drugs and future clinical trials in primary progressive multiple sclerosis.

A model-based quantitative analysis of efficacy and associated factors of platelet rich plasma treatment for osteoarthritis.

OBJECTIVE: While platelet rich plasma (PRP) has been extensively studied in treating osteoarthritis (OA), there has been an ongoing debate regarding the efficacy of PRP and the optimal subpopulation for PRP treatment remains unknown. The authors hereby aim to establish a pharmacodynamic model-based meta-analysis to quantitatively evaluate PRP efficacy, comparing with hyaluronic acid (HA) and identify relevant factors that significantly affect the efficacy of PRP treatment for OA. METHODS: The authors searched for PubMed and the Cochrane Library Central Register of Controlled Trials of PRP randomized controlled trials (RCTs) for the treatment of symptomatic or radiographic OA from the inception dates to 15 July 2022. Participants' clinical and demographic characteristics and efficacy data, defined as Western Ontario and McMaster Universities Osteoarthritis Index and visual analog scale pain scores at each time point were extracted. RESULTS: A total of 45 RCTs (3829 participants) involving 1805 participants injected with PRP were included in the analysis. PRP reached a peak efficacy at ~ 2-3 months after injection in patients with OA. Both conventional meta-analysis and pharmacodynamic maximal effect models showed that PRP was significantly more effective than HA for joint pain and function impairment (additional decrease of 1.1, 0.5, 4.3, and 1.1 scores compared to HA treatment at 12 months for Western Ontario and McMaster Universities Osteoarthritis Index pain, stiffness, function, and visual analog scale pain scores, respectively). Higher baseline symptom scores, older age (≥60 years), higher BMI (≥30), lower Kellgren-Lawrence grade (≤2) and shorter OA duration (<6 months) were significantly associated with greater efficacy of PRP treatment. CONCLUSION: These findings sugges t that PRP is a more effective treatment for OA than the more well-known HA treatment. The authors also determined the time when the PRP injection reaches peak efficacy and optimized the targeting subpopulation of OA. Further high-quality RCTs are required to confirm the optimal population of PRP in the treatment of OA.

Comparison on the effect of seven drugs to prevent relapses of neuromyelitis optica spectrum disorders: A modeling analysis of literature aggregate data.

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) is an immune-mediated demyelinating disease of the central nervous system. This study aimed to perform a comprehensive comparison of the effect of seven drugs to prevent relapses of NMOSD. METHOD: A literature search was conducted using public databases. Clinical studies on the seven drugs (eculizumab, inebilizumab, satralizumab, rituximab, tocilizumab, azathioprine, and mycophenolate mofetil) to prevent relapses of NMOSD were identified. A time-course model was established using the time to first relapse as the primary endpoint, in order to evaluate the long-term effect of each drug in preventing relapse. RESULTS: Twenty-four trials, including 2207 patients, were included in the model analysis. The results showed that monoclonal antibody therapy could significantly prolong the time to first relapse. Among all seven drugs, eculizumab can most significantly prevent patient from relapse. The estimated proportion of relapse-free patients treated with eculizumab was 98.9% at 24 months. CONCLUSION: Based on the construction of a time-course pharmacodynamic model, this study made a comprehensive quantitative comparison of seven drugs for the treatment of NMOSD for the first time. These results can not only serve as a quantitative supplement for the rational use of drugs in clinical practice but also provide a pharmacodynamic reference for clinical trial design and decision making in the future.

Quantitative Comparison of the Clinical Efficacy of 6 Classes Drugs for IgA Nephropathy: A Model-Based Meta-Analysis of Drugs for Clinical Treatments.

Introduction: There is a wide variety of drugs for the clinical treatment of immunoglobulin A (IgA) nephropathy; however, previous studies have failed to clarify the quantitative differences in the efficacy of various drugs. In this study, we aimed to quantitatively compare the clinical efficacy of 6 classes of drugs with different pharmacological mechanisms for the treatment of IgA nephropathy and to identify relevant influencing factors. Methods: Clinical trials of drugs for the treatment of IgA nephropathy were obtained from public databases. The change in daily urinary protein excretion from baseline was used as the efficacy index, and the time-effect model was established using a model-based meta-analysis method. Based on the final model, the typical efficacy was simulated, and the differences in efficacy were compared. Results: A total of 40 studies with 2288 subjects were included in this study. The results showed that the time-effect relationship of the placebo and 6 classes of drugs was consistent with the Emax model. The placebo reduced urinary protein excretion by up to 0.44 g/day, and it took more than 27 months to reach half of its maximum effect. The onset of the 6 classes of drugs were the same; they all reached half of their maximum effect after 5.59 months. More importantly, we found a significant influence of urinary protein baseline on drug efficacy, as indicated by an increase of 0.63 g/day in the theoretical maximum effect of drugs for every 1 g/day increase in urinary protein baseline. After correcting for the urinary protein baseline, the order of efficacy of the 6 classes of drugs was as follows: corticosteroids > immunosuppressants > other drugs > renin-angiotensin system blockers > antiplatelet agents > N-3 fatty acids. Conclusion: This study provides the first comprehensive quantitative analysis of the differences in the efficacy of 6 classes of drugs with different pharmacological mechanisms for treating IgA nephropathy. The results of this study provide an important reference for the rational clinical use of drugs for IgA nephropathy, and also provide a reliable efficacy standard for the development of new drugs for IgA nephropathy.

Placebo Response to Oral Administration in Osteoarthritis Clinical Trials and Its Associated Factors: A Model-Based Meta-analysis.

Importance: In osteoarthritis (OA) clinical trials, a placebo is often used as control. Therefore, a thorough understanding of the placebo response is important for guiding drug development in OA. Objective: To develop an oral placebo response model for OA. Data Sources: PubMed, EMBASE, and Cochrane Library databases were searched systematically from January 1, 1991, to July 2, 2022. Study Selection: Randomized double-blind placebo-controlled trials of patients with primary OA were included. The interventions and placebo were administered orally. A total of 3032 trials were identified; of these, 130 (4.3%) met the inclusion criteria. Data Extraction and Synthesis: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, dosage form of the placebo, sample size, proportion of patients who previously used nonsteroidal anti-inflammatory drugs, publication year, intervention categories, Kellgren-Lawrence grades, proportion of White patients, duration of pain, funding source, and risk of bias were extracted. A model-based meta-analysis was used to evaluate the time course of the placebo response in OA treatment and estimate the influencing factors. For subgroup analyses, a meta-analysis with a random-effects model was used to summarize the typical values of the model parameters and their SEs. Main Outcomes and Measures: The primary end point was the time course of the oral placebo response on the WOMAC pain, stiffness, and function subscale scores. Results: The 130 trials selected for analysis included 12 673 participants (mean age, 59.9 years; 68.9% women). The baseline scores of WOMAC pain, stiffness, and function subscales were found to be significantly associated with the placebo response. The placebo response reached 90% of its maximum response between 5 and 7 weeks. The placebo responses on the WOMAC subscales were also associated with the sample size, proportion of patients who had previously used nonsteroidal anti-inflammatory drugs, intervention drugs, and publication year. Conclusions and Relevance: In this study, an oral placebo response model of OA was developed that may quantitatively describe the placebo response at different baseline levels of symptoms. The findings may provide valuable references for future clinical trial design and decision-making.