Bioequivalence of two tacrolimus 1-mg formulations under fasting conditions in healthy subjects: A randomized, two-period crossover trial
.

OBJECTIVE: The present study compared the pharmacokinetics of two (1 mg) tacrolimus formulations (test (generic from Panacea) and reference (innovator from Astellas)) after a single-dose administration as per the European Medicine Agency (EMA) guidelines to grant marketing authorization. MATERIALS AND METHODS: This study was a randomized, open-label, balanced, two-treatment, two-period, two-sequences, single-dose, truncated-area, crossover design with a washout period of 19 days between the phases. Healthy subjects aged 18 - 45 years (both inclusive) were included. Eligible subjects received a single oral dose of 5 × 1-mg capsule of tacrolimus either test or reference formulation. Blood samples were collected until 72.00 hours postdose, and peak concentration (Cmax) and area under the curve (AUC0-72) were evaluated in whole blood using validated LC-MS/MS. Safety was also assessed in each period. RESULTS: Of 56 subjects enrolled, 52 completed both study periods. The arithmetic mean (SD) Cmax for the reference and test formulations was 40.62 (11.30) and 46.20 (10.73) ng/mL, and AUC0-72 was 348.34 (156.41) and 361.04 (158.71) ng×h/mL, respectively. The geometric least square mean ratio (90% confidence interval (CI)) was 115.07% (90% CI: 109.81, 120.59) for Cmax and 103.78 (90% CI: 97.40, 110.58) for AUC0-72, which fell within the acceptance range as per EMA guidelines for narrow therapeutic index drugs (Cmax: 80.00 - 125.00%; AUC: 90.00 - 111.11%). No serious adverse event was observed. CONCLUSION: The generic tacrolimus was bioequivalent to the reference formulation, was well tolerated, and provides a well-acceptable alternative to the reference drug. Switching treatment to generic tacrolimus medication may reduce the cost and economic burden of treating transplanted patients.

Immunogenicity of a new routine vaccination schedule for global poliomyelitis prevention: an open-label, randomised controlled trial.

BACKGROUND: Polio eradication needs a new routine immunisation schedule--three or four doses of bivalent type 1 and type 3 oral poliovirus vaccine (bOPV) and one dose of inactivated poliovirus vaccine (IPV), but no immunogenicity data are available for this schedule. We aimed to assess immunogenicity of this vaccine schedule. METHODS: We did an open-label, randomised controlled trial in four centres in India. After informed consent was obtained from a parent or legally acceptable representative, healthy newborn babies were randomly allocated to one of five groups: trivalent OPV (tOPV); tOPV plus IPV; bOPV; bOPV plus IPV; or bOPV plus two doses of IPV (2IPV). The key eligibility criteria were: full-term birth (≥37 weeks of gestation); birthweight ≥2·5 kg; and Apgar score of 9 or more. OPV was administered at birth, 6 weeks, 10 weeks, and 14 weeks; IPV was administered intramuscularly at 14 weeks. The primary study objective was to investigate immunogenicity of the new vaccine schedule, assessed by seroconversion against poliovirus types 1, 2, and 3 between birth and 18 weeks in the per-protocol population (all participants with valid serology results on cord blood and at 18 weeks). Neutralisation assays tested cord blood and sera collected at 14 weeks, 18 weeks, 19 weeks, and 22 weeks by investigators masked to group allocation. This trial was registered with the India Clinical Trials Registry, number CTRI/2013/06/003722. FINDINGS: Of 900 newborn babies enrolled between June 13 and Aug 29, 2013, 782 (87%) completed the per-protocol requirements. Between birth and age 18 weeks, seroconversion against poliovirus type 1 in the tOPV group occurred in 162 of 163 (99·4%, 95% CI 96·6-100), in 150 (98·0%, 94·4-99·6) of 153 in the tOPV plus IPV group, in 153 (98·7%, 95·4-99·8) of 155 in the bOPV group, in 155 (99·4%, 96·5-100) of 156 in the bOPV plus IPV group, and in 154 (99·4%, 96·5-100) of 155 in the bOPV plus 2IPV group. Seroconversion against poliovirus type 2 occurred in 157 (96·3%, 92·2-98·6) of 163 in the tOPV group, 153 (100%, 97·6-100·0) of 153 in the tOPV plus IPV group, 29 (18·7%, 12·9-25·7) of 155 in the bOPV group, 107 (68·6%, 60·7-75·8) of 156 in the bOPV plus IPV group, and in 121 (78·1%, 70·7-84·3) of 155 in the bOPV plus 2IPV group. Seroconversion against poliovirus type 3 was achieved in 147 (90·2%, 84·5-94·3) of 163 in the tOPV group, 152 (99·3%, 96·4-100) of 153 in the tOPV plus IPV group, 151 (97·4%, 93·5-99·3) of 155 in the bOPV group, 155 (99·4%, 96·5-100) of 156 in the bOPV plus IPV group, and 153 (98·7%, 95·4-99·8) of 155 in the bOPV plus 2IPV group. Superiority was achieved for vaccine regimens including IPV against poliovirus type 3 compared with those not including IPV (tOPV plus IPV vs tOPV alone, p=0·0008; and bOPV plus IPV vs bOPV alone, p=0·0153). 12 serious adverse events occurred (six in the tOPV group, one in the tOPV plus IPV group, three in the bOPV group, zero in the bOPV plus IPV group, and two in the bOPV plus 2IPV group), none of which was attributed to the trial intervention. INTERPRETATION: The new vaccination schedule improves immunogenicity against polioviruses, especially against poliovirus type 3. FUNDING: WHO, through a grant from Rotary International (grant number 59735).

The Immunogenicity of Monovalent Oral Poliovirus Vaccine Type 1 (mOPV1) and Inactivated Poliovirus Vaccine (IPV) in the EPI Schedule of India.

BACKGROUND: In 2016, the Global Polio Eradication Initiative (GPEI) recommended the cessation of using type 2 oral poliovirus vaccine (OPV) and OPV, with countries having to switch from the trivalent to bivalent OPV (bOPV) with the addition of inactivated poliovirus vaccine (IPV) in their routine immunization schedule. The current GPEI strategy 2022-2026 includes a bOPV cessation plan and a switch to IPV alone or a combination of vaccine schedules in the future. The focus of our study was to evaluate the immunogenicity of monovalent OPV type 1 (mOPV1) with IPV and IPV-only schedules. METHODS: This was a three-arm, multi-center randomized-controlled trial conducted in 2016-2017 in India. Participants, at birth, were randomly assigned to the bOPV-IPV (Arm A) or mOPV1-IPV (Arm B) or IPV (Arm C) schedules. Serum specimens collected at birth and at 14, 18, and 22 weeks old were analyzed with a standard microneutralization assay for all the three poliovirus serotypes. RESULTS: The results of 598 participants were analyzed. The type 1 cumulative seroconversion rates four weeks after the completion of the schedule at 18 weeks were 99.5% (97.0-99.9), 100.0% (97.9-100.0), and 96.0% (92.0-98.1) in Arms A (4bOPV + IPV), B (4mOPV1 + IPV), and C (3IPV), respectively. Type 2 and type 3 seroconversions at 18 weeks were 80.0% (73.7-85.1), 76.9% (70.3-82.4); 93.2% (88.5-96.1), 100.0% (98.0-100.0); and 81.9% (75.6-86.8), 99.4% (96.9-99.9), respectively, in the three arms. CONCLUSIONS: This study shows the high efficacy of different polio vaccines for serotype 1 in all three schedules. The type 1 seroconversion rate of mOPV1 is non-inferior to bOPV. All the vaccines provide high type-specific immunogenicity. The program can adopt the use of different vaccines or schedules depending on the epidemiology from time to time.

Safety and immunogenicity of a single dose, live-attenuated 'tetravalent dengue vaccine' in healthy Indian adults; a randomized, double-blind, placebo controlled phase I/II trial.

BACKGROUND: Dengue fever is the most prevalent mosquito-borne viral disease in the world, with 390 million dengue infections occurring every year. There is an unmet medical need to develop a safe, effective and affordable dengue vaccine against all four Dengue serotype viruses-DENV1, DENV-2, DENV-3 and DENV-4. Panacea Biotec Ltd (PBL) has developed a cell culture-derived, live-attenuated, lyophilized Tetravalent Dengue Vaccine (TDV). Here, in phase I/II study we assessed the safety and immunogenicity of single dose 'Dengue Tetravalent Vaccine' in healthy Indian adults. METHODS: In the study, 100 healthy adult volunteers aged 18-60 years were enrolled. The participants were allocated to TDV and placebo groups in 3:1 ratio, i.e. 75 participants to TDV group and 25 participants to the placebo group. Enrolled participants were administered a single dose of 0.5 ml of the test vaccine / placebo by subcutaneous route. Primary outcome for safety included all solicited AEs up to 21 days, unsolicited AEs up to 28 days and all AEs/serious adverse events (SAEs) till day 90 post-vaccination. For immunogenicity assessment the primary outcome was seroconversion & seropositivity rate by PRNT50 to all four serotype till 90 days. RESULTS: Overall, 100 subjects were vaccinated out of which 8 subjects (5 subjects in vaccine group and 3 subjects in placebo group) dropped out from the study. The most commonly reported solicited local AE was pain and most common solicited systemic AE was headache and fever. No SAE was reported during the study. There was no statistically significant difference between TDV and placebo groups in terms of AEs. Of the 92 subjects who completed all scheduled visits in the study, 59 (81.9%) achieved seroconversion for DENV-1, 56 (77.8%) for DENV-2; 59 (81.9%) for DENV-3 and 57 (79.2%) for DENV-4 in TDV group. The seroconversion rate in the TDV group was statistically significant (p < 0.001) compared to placebo.Clinical trial registration: CTRI/2017/02/007923.

Immunogenicity of Fractional Dose Inactivated Poliovirus Vaccine in India.

INTRODUCTION: Following the withdrawal of Sabin type 2 from trivalent oral poliovirus vaccine (tOPV) in 2016, the introduction of ≥1 dose of inactivated poliovirus vaccine (IPV) in routine immunization was recommended, either as 1 full dose (0.5mL, intramuscular) or 2 fractional doses of IPV (fIPV-0.1mL, intradermal). India opted for fIPV. We conducted a comparative assessment of IPV and fIPV. METHODS: This was a 4-arm, open-label, multicenter, randomized controlled trial. Infants were enrolled and vaccines administered according to the study design, and the blood was drawn at age 6, 14, and 18 weeks for neutralization testing against all 3 poliovirus types. RESULTS: Study enrolled 799 infants. The seroconversion against type 2 poliovirus with 2 fIPV doses was 85.8% (95% confidence interval [CI]: 80.1%-90.0%) when administered at age 6 and 14 weeks, 77.0% (95% CI: 70.5-82.5) when given at age 10 and 14 weeks, compared to 67.9% (95% CI: 60.4-74.6) following 1 full-dose IPV at age 14 weeks. CONCLUSION: The study demonstrated the superiority of 2 fIPV doses over 1 full-dose IPV in India. Doses of fIPV given at 6 and 14 weeks were more immunogenic than those given at 10 and 14 weeks. Clinical Trial Registry of India (CTRI). Clinical trial registration number was CTRI/2017/02/007793.

A randomized, open label trial to evaluate and compare the immunogenicity and safety of a novel liquid hexavalent DTwP-Hib/Hep B-IPV (EasySix™) to licensed combination vaccines in healthy infants.

Immunogenicity and safety of a newly developed liquid DTwP-Hib/HepB-IPV hexavalent vaccine (EasySix™) was evaluated and compared with administration of commercially licensed Pentavac SD® (DTwP-HepB/Hib) and Imovax Polio® vaccine in an open-label, randomized multi-centric trial. 284 participants, aged 6-10weeks, randomized in a 1:1 allocation, received three doses of test or comparator vaccines, administered 4weeks apart. Immunogenicity of the vaccines was determined by measuring the baseline and post-vaccination antibody responses and comparing the proportions of subjects achieving seroprotection against the vaccine antigens; safety was evaluated in terms of solicited (local and systemic) and unsolicited incidences in the follow up phase. Post-vaccination, seroprotection was achieved against all six vaccine antigens in both vaccine groups. The seroresponse rate as well as geometric mean titers of antibody for all vaccine components were comparable between EasySix™ and Pentavac SD®-Imovax Polio® group. Both vaccines had similar reactogenicity profiles and were well tolerated; all adverse events resolved completely without any sequelae. Only one serious adverse event was reported that completely resolved; it was regarded unconnected to the vaccine administered. This study demonstrated that immunogenicity and safety profiles of EasySix™ vaccine, manufactured by Panacea Biotec Ltd, are non-inferior to the commercially available vaccines. CLINICAL TRIAL REGISTRATION: CTRI/2015/02/005578.

A randomized, open-label clinical trial to evaluate immunogenicity and safety of an indigenously developed DTwP-Hib tetravalent combination vaccine (Easyfour®-TT) with Quadrovax® in Indian infants.

An open-label, randomized, multi-center trial was conducted to compare the immunogenicity and safety of an indigenously developed tetravalent DTwP-Hib vaccine, Easyfour®-TT with a commercially available vaccine, Quadrovax®. A total of 244 infants in good health, aged 6-10 weeks, were randomized in a 1:1 allocation to receive three doses of the test or comparator vaccine. Immunogenicity of the vaccines was determined by measuring the baseline and post-vaccination antibody response against the vaccine antigens; safety was evaluated in terms of local and systemic reactions (solicited and unsolicited) reported during the trial. Similar levels of seroprotection/seroresponse were achieved, 4 weeks after receiving 3 doses of Easyfour®-TT and Quadrovax®, and the antibody response of Easyfour®-TT was found non-inferior to Quadrovax®, against all four vaccine antigens. Both vaccines were well tolerated and had similar reactogenicity profiles, with a significantly lower occurrence of local (redness at injection site) and systemic reactions (irritability post-vaccination) with Easyfour®-TT vaccine as compared to Quadrovax® (p < 0.05). All adverse events resolved completely with no sequelae. All through the study, only one serious adverse event was observed that completely resolved upon treatment and was deemed unrelated to the vaccine administered. This study demonstrated that Easyfour®-TT vaccine was safe and immunogenic. CLINICAL TRIAL REGISTRATION NUMBER: CTRI/2014/12/005326 (registered with the Clinical Trial Registry of India (CTRI)).