Safety of low dose efavirenz regimen in Indian adults with HIV-1 infection: Insights from a phase 4 interventional randomised trial.

BACKGROUND: A randomized interventional phase 4 study in the Indian population confirmed the non-inferiority of the combination tenofovir/lamivudine/efavirenz (TLE)-400 to TLE600. The current manuscript describes in detail the safety profile and patient-reported safety outcomes obtained from the phase 4 study. METHODS: This investigation was part of a phase 4 non-inferiority study with a blinded assessment, conducted across 17 sites in India. The duration of the study was 24 weeks. Safety endpoints assessed included all the adverse events (AEs) related to the study treatment (TLE400 and TLE600). The depression anxiety stress 21-item scale questionnaire and efavirenz-related symptom questionnaire were also used to measure depression, anxiety, stress, and patient experience. RESULTS: A total of 68 patients (52.3%) reported 261 AEs and 87 patients (64.9%) reported 379 AEs related to study treatment in TLE400 group and TLE600 group respectively, P = .037. The reported AEs associated with central nervous system disorders were lower in the TLE400 group with 41 patients (31.5%) to 61 patients (45.5%) in the TLE600 group. The change from mean baseline value for depression anxiety stress 21-item scale at week 28 in TLE400 group and TLE600 group was -5.1 and -6.2 respectively. Similarly, the mean change from baseline score of efavirenz-related symptoms at week 28 in TLE400 group and TLE600 group were -5.1 and -4.1 respectively. CONCLUSION: The low dose efavirenz (400 mg) in combination with tenofovir and lamivudine had a better safety and tolerability profile than the standard dose of efavirenz (600 mg) in combination with tenofovir and lamivudine. Thus, low dose efavirenz should be preferred over the standard dose.

Efficacy and safety of 400 mg efavirenz versus standard 600 mg dose when taken with tenofovir and lamivudine combination in Indian adult patients with HIV-1 infection: An open-label, interventional, randomized, non-inferiority trial.

BACKGROUND: To evaluate the non-inferiority of low dose efavirenz (400 mg) to standard dose efavirenz (600 mg), when taken in combination with tenofovir and lamivudine in Indian patients with HIV-1 infection. METHODS: An open-label, interventional phase IV study with blinded assessment was conducted across 17 sites in India. HIV-1-infected antiretroviral therapy-naive adult patients (≥18 years of age) with a plasma HIV-1 viral load of at least 1000 copies per mL were randomized to receive either tenofovir/lamivudine/efavirenz (TLE) 400 or TLE 600. The primary endpoint was the difference in the proportion of patients achieving < 200 copies per mL at the end of 24 weeks. RESULTS: A total of 265 patients were enrolled and were randomized in 1:1 ratio to TLE 400 group (130 patients) and TLE 600 group (135 patients). At week 24, the proportion of patients with a viral load of less than 200 copies per mL was 80.70% for TLE 400 and 78.95% for TLE 600 (difference 1.75%, 90% confidence interval: -7.01, 10.49) which was within the predefined margin of -10% (90% confidence interval). Significantly lower study drug-related adverse events were observed in TLE 400 group compared to TLE 600 group (52.30%, n = 68 vs 64.92%, n = 87; P = .037). The treatment discontinuation percentage was marginally higher by 2.08% in TLE 600 group. CONCLUSION: The fixed-dose combination of TLE 400 is non-inferior to TLE 600 in terms of viral suppression and has an improved safety profile over 24 weeks in adult Indian patients with HIV-1 infection.

A Phase IV Study on Safety, Tolerability and Efficacy of Dolutegravir, Lamivudine, and Tenofovir Disoproxil Fumarate in Treatment Naïve Adult Indian Patients Living with HIV-1.

Purpose: WHO recommends dolutegravir (DTG) based regimens as first-line treatment for HIV-1 infection. However, few studies have been conducted in Indian population. Hence, our study evaluated the safety, tolerability, and efficacy of DTG 50 mg with Tenofovir and Lamivudine (300/300mg) fixed dose combination in treatment naïve adult Indian patients. Methods: This was an open label, multicenter, prospective, interventional, phase IV study conducted across 14 sites between February 2019 and July 2020. 24 weeks was the treatment duration for each subject. The primary end point was to assess the incidence of adverse events (AEs) and secondary end points were to assess the proportion of patients achieving plasma HIV-1 RNA levels <50 copies/mL at week 24 and change in CD4+ cell count from the baseline. Safety analysis was conducted using Safety Analysis Set and efficacy analysis was carried out using Full Analysis Set and Per protocol set. Results: A total of 288 patients were screened; 250 were enrolled; and 229 completed the study. 389 AEs were reported from 58% of patients. Of these, 61 were related to study treatment. One event of decreased creatinine clearance led to study discontinuation. One serious event of pyrexia was reported, which was unrelated to the study drug. The most common AEs were headache (18%), pyrexia (14%), vomiting (6.4%) and upper respiratory tract infections (6%). No deaths were reported. At week 24, 86.8% of the patients achieved plasma HIV-1 RNA levels <50 copies/mL and the mean CD4 cell count increased from 350.2 (SD, 239.73) at baseline to 494.6 (SD, 261.40) with an average increase of 143.2 (SD, 226.14) cells. Conclusion: This study demonstrated the safety and efficacy of DTG based regimen in treatment naïve HIV-1 patients in Indian population and support use of DTG as first-line treatment regimen.

Efficacy of green jackfruit flour as a medical nutrition therapy replacing rice or wheat in patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled study.

BACKGROUND/OBJECTIVES: Medical nutrition therapy along with pharmacological interventions as a multidisciplinary approach is required to treat type 2 diabetes mellitus (T2DM). This study evaluated the efficacy of Jackfruit365™ green jackfruit flour as an integral part of daily meal in patients with T2DM. SUBJECTS/METHODS: This was a randomized, double-blind, placebo-controlled study conducted between May 2019 and February 2020. Patients of either sex aged ≥18 to ≤60 years with a diagnosis of T2DM for >1 year receiving oral antihyperglycemic agents were randomized (1:1) to receive either jackfruit flour 30 g/day (Group A) or placebo flour (Group B) (breakfast and dinner) daily for 12 weeks replacing an equal volume of rice or wheat flour. The primary endpoint was a mean change in glycosylated hemoglobin (HbA1c). Other endpoints were mean changes in fasting plasma glucose (FPG), postprandial plasma glucose (PPG), lipid profile, and body weight. The independent t-test was used to compare changes between the groups. RESULTS: A total of 40 patients were enrolled (n = 20 each). A significantly higher reduction in HbA1c was observed in Group A compared to Group B from baseline to week 12 [-2.73 mmol/mol (-0.25%) vs. 0.22 mmol/mol (0.02%), p = 0.006]. The mean change in FPG and PPG was significantly higher in Group A than that of Group B (p = 0.043 and p = 0.001). The continuous glucose monitoring showed decreasing mean blood glucose in 7 days of administration of jackfruit flour meal. CONCLUSION: Patients from Group A had a significantly higher reduction in HbA1c, FPG, and PPG than Group B demonstrating the efficacy of jackfruit flour in glycemic control as medical nutrition therapy replacing an equal volume of rice or wheat flour in daily meal. CLINICAL TRIAL REGISTRY: CTRI/2019/05/019417.

Evaluation of the Efficacy and Safety of Azilsartan in Adult Patients with Essential Hypertension: A Randomized, Phase-III Clinical Study in India.

BACKGROUND: Globally, women and men over the age of 25 years suffer from hypertension, the need for new treatment strategies to treat hypertension is due to the multi-faceted nature of the disease. Lack of optimal blood pressure control can lead to multiple complications. Therefore, this phase 3 study was conducted to assess the efficacy, safety and tolerability of potential product azilsartan hydrochloride for reduction in blood pressure in Indian patients with essential hypertension. METHODS: This was a prospective, multicentre, randomized, comparative, parallel study of 303 participants over six weeks of treatment period with either azilsartan 40 mg or azilsartan 80 mg or telmisartan 40 mg in adult patients with essential hypertension. The primary endpoint was the change in mean trough sitting clinic systolic blood pressure (scSBP) from baseline to week 6. The secondary endpoints were the change in mean trough sitting clinic diastolic blood pressure (scDBP) from baseline and change in the 24-hour mean ambulatory systolic blood pressure (SBP)and diastolic blood pressure (DBP) from baseline. RESULTS: The change in mean trough scSBP from baseline to week 6 was -27.2 ± 9.99, -28.2 ± 10.06 and -26.7 ± 9.72 (Per Patient (PP) Population) and -27.2 ± 9.93, -28.3 ± 10.01 and -26.7 ± 9.67 (Intent to Treat (ITT) Population) in the azilsartan 40mg, 80mg and telmisartan 40mg groups respectively. The lower limit of 95% CI of difference in change in mean systolic blood pressure was -2.35(Azilsartan 40mg) and 1.32 (Azilsartan 80mg) is less than the non-inferiority margin (i.e. 2.67). The change in mean trough scDBP from baseline to week 6 was -13.1 ± 8.46, -12.9 ± 7.20, and -13.0 ± 7.96 (PP) and -13.1 ± 8.42, -12.9 ± 7.16 and -13.0 ± 7.92 (ITT) in Azilsartna 40 mg, Azilsartan 80 mg and Telmisartan 40 mg respectively. The reduction in trough scDBP in Azilsartan 40 mg (p=0.9461: PP; p=0.9330: ITT) and Azilsartan 80 mg (p=0.9090: PP; p=0.9158: ITT) was not statistically significant compared to Telmisartan 40 mg. The difference in fall in the trough scSBP, scDBP and ambulatory SBP and DBP was similar between the groups from baseline to week 6 (P >0.05). Headache and dizziness were the most frequent treatmentrelated treatment-emergent adverse events. CONCLUSION: Azilsartan is an effective blood pressure lowering drug and well tolerated and was non- inferior to telmisartan in its safety and efficacy.