Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202010705577776 Date of Approval: 14/10/2020
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title A phase 3, double-blind, randomized, controlled trial to assess the safety of a novel type 2 oral polio vaccine (nOPV2) in infants and young children and lot-to-lot consistency of the immune response to nOPV2 in infants in The Gambia
Official scientific title A phase 3, double-blind, randomized, controlled trial to assess the safety of a novel type 2 oral polio vaccine (nOPV2) in infants and young children and lot-to-lot consistency of the immune response to nOPV2 in infants in The Gambia
Brief summary describing the background and objectives of the trial The overriding aim of the nOPV2 project is to develop a novel, more genetically stable version of type 2 oral poliovirus vaccine.1 The project is motivated by rare, but serious cases of vaccine-associated paralytic polio (VAPP) that can occur following vaccination with Sabin-containing OPV, as well as the spread of associated vaccine-derived polioviruses (VDPVs).2 Central to both VAPP and disease induced by VDPVs is reversion of the vaccine strain to a more neurovirulent phenotype, which occurs during replication in vaccine recipients. These reverted viruses can either cause disease in the vaccinee or be transmitted by the fecal-oral route to contacts or community members. In addition, the ability of VDPVs to survive in the environment and be transmitted to others without being detected through acute flaccid paralysis surveillance, given most infections are asymptomatic, is a major risk to the entire polio eradication effort.3 The continued circulation of type 2 VDPV, with the spread and emergence of outbreaks in excess of predictions, taxing stores of mOPV2 while simultaneously heightening concern about the use of mOPV2 to combat these outbreaks, lends greater urgency to the efforts to assess and make available an immunogenic oral polio vaccine that is more genetically stable than mOPV2.2 4 1 The candidate vaccine to be assessed in this study has been developed through genetic modification of the Sabin type 2 strain used in monovalent OPV (mOPV2) and previously in trivalent OPV (tOPV). The goal has been to retain similar immunogenicity and antigenicity to the parental Sabin strain in mOPV2 while achieving significantly less potential to revert to virulence. Safety assessment in phase 1 and 2 trials in adults in Belgium and young children and infants in Panama has been favorable, and the candidate vaccine has been demonstrated to be at least as immunogenic and more phenotypically stable than mOPV2 (See Section 1.5 and IB)5. The overall objectives of the overall nOPV2 program are (1) to achieve licensure and World Health Organization (WHO) prequalification of nOPV2, with an indication for active immunization against infection caused by poliomyelitis virus type 2; (2) to provide sufficient evidence to support a policy decision to stockpile (and deploy for control of outbreaks) the nOPV2 vaccine in lieu of the current mOPV2, and (3) to potentially make nOPV2 available pre-licensure during outbreaks, provided the data from the phase 1 and 2 studies demonstrate appropriate safety and immunogenicity. This study will provide additional safety data, assessment of consistency of response to three different lots of nOPV2 in infants and additional data on immune response in young children in support of licensure by regulatory authorities in Indonesia and subsequent prequalification by the WHO.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) nOPV2
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied Polio
Purpose of the trial Prevention: Vaccines
Anticipated trial start date 04/01/2021
Actual trial start date 11/02/2021
Anticipated date of last follow up 07/02/2022
Actual Last follow-up date 03/02/2022
Anticipated target sample size (number of participants) 2945
Actual target sample size (number of participants) 2945
Recruitment status Completed
Publication URL
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Factorial: participants randomly allocated to either no, one, some or all interventions simultaneously Randomised Permuted block randomization Central randomisation by phone/fax Masking/blinding used Care giver/Provider
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Control Group nopv2 nOPV2 Lot 1, nOPV2 Lot 2, nOPV Lot 2 113 days Table 11: Study Schema Age-group Study product Total group size* Study Arm Single dose** Two dose and reactogenicity cohorts*** Infant (≥18 to <52 weeks old) nOPV2, lot 1 670 1a 446 1b 224 nOPV2, lot 2 670 2a 446 2b 224 nOPV2, lot 3 670 3a 446 3b 224 bOPV 335 4a 223 4b 112 Young children (≥1 to <5 years old) nOPV2 300 5 300 bOPV 300 6 300 Total population 2,945 *All enrolled subjects will provide venous bloods samples (approximately 3mL) at baseline and day 29 **A subset of infant subjects receiving a single dose of study vaccine will provide stool samples at baseline, 7-, 28- and 84-days following vaccination (approximately 100/arm for infants receiving nOPV2 [total of 300] and 50 infants receiving bOPV) ***All infants and young children receiving two doses of study vaccine will participate in a reactogenicity cohort the 7 days following each vaccination. They will also provide an additional blood sample at day 57. 2945 Placebo
Experimental Group nopv2 vaccine Study novel oral polio vaccine (nOPV): • Novel type 2 OPV candidate (nOPV2), containing ≥105.0 CCID50/dose (0.1 mL, 2 drops), manufactured by Bio Farma, Indonesia. The candidate vaccine is a live, attenuated serotype-2 poliovirus derived from a modified Sabin type-2 infectious cDNA clone and propagated in Vero cells. Modifications were introduced in the viral nucleotide sequences in part of the 5ʹ-untranslated region to improve the genetic stability of this major attenuating determinant of Sabin type-2, and two modifications were made in the 3D polymerase to further improve stability of the attenuation and reduce recombination. In addition, a key replication element from the 2C coding region was relocated to the 5ʹ-untranslated region to reduce the risk of loss of stabilized 5’ UTR through recombination. The vaccine formulation also includes sucrose, acetic acid or NaHCO3, and Basal Medium Eagle (BME) solution. The candidate vaccine is yellow to pink solution and is to be stored at ≤-20oC until thawed (and kept at 2-8oC prior to administration). For this trial, thawed vaccine can be maintained at 2-8oC for up to two weeks prior to administration. 113 days Novel type 2 OPV candidate (nOPV2), containing ≥105.0 CCID50/dose (0.1 mL, 2 drops), manufactured by Bio Farma, Indonesia. The candidate vaccine is a live, attenuated serotype-2 poliovirus derived from a modified Sabin type-2 infectious cDNA clone and propagated in Vero cells. Modifications were introduced in the viral nucleotide sequences in part of the 5ʹ-untranslated region to improve the genetic stability of this major attenuating determinant of Sabin type-2, and two modifications were made in the 3D polymerase to further improve stability of the attenuation and reduce recombination. In addition, a key replication element from the 2C coding region was relocated to the 5ʹ-untranslated region to reduce the risk of loss of stabilized 5’ UTR through recombination. The vaccine formulation also includes sucrose, acetic acid or NaHCO3, and Basal Medium Eagle (BME) solution. The candidate vaccine is yellow to pink solution and is to be stored at ≤-20oC until thawed (and kept at 2-8oC prior to administration). For this trial, thawed vaccine can be maintained at 2-8oC for up to two weeks prior to administration. 2610
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
1. Age: • Infants: ≥18 and <52 weeks at the time of first study vaccination (126 days through the day before their first birthday, inclusive, with the day after birth considered 1-day old) • Young children: ≥1 to <5 years old at the time of the first study vaccination (from the first birthday up to the day prior to the fifth birthday) 2. The subject’s parent must be judged to be willing and able to provide informed consent based on the content of the informed consent document and signed/thumb-printed informed consent must be provided . 3. Intention of the subjects’ parents to remain in the study area with the infant/young child during the study period 4. The subject must have a readily identifiable place of residence in the study area 5. Infants: prior receipt of full primary series of bOPV and a single dose of IPV prior to randomization, with IPV dose at least 4 weeks prior to randomization 6. Young children: prior receipt of at least one dose of type 2-containing vaccine (IPV, tOPV or mOPV2), with the last dose of type 2-containing vaccine at least 4 weeks prior to the day of first study vaccination [Young children who have not received type 2 containing vaccine may receive IPV and become eligible to be randomized to receive study vaccine 4 weeks after receipt of IPV.] 7. Parent ability and willingness to comply with the required study procedures, including the home visits, clinic visits, assessment and sampling procedures, as judged by the investigator 8. Parent willingness to contact the study team in the event of an acute illness 9. Willingness not to use herbal and other traditional medications for the duration of the study 10. Infant Welfare Card (IWC) is available 11. Baseline peripheral blood sample obtained from the infant/young child that is sufficient to allow the primary trial immunogenicity endpoints to be evaluated 1. Moderate or severe (grade ≥ 2) acute illness at the time of enrollment/first study vaccination – temporary exclusion (see Appendix 2: Severity Grading Tables) o Subject with mild (grade 1) acute illnesses may be enrolled at the discretion of the investigator 2. Presence of fever on the day of enrollment/first study vaccination (axillary temperature ≥37.5oC) – temporary exclusion 3. Presence of abnormal vital signs (respiratory rate and/or heart rate) for age on the day of enrollment/first study vaccination – temporary exclusion 4. Receipt of any investigational medicinal product within six months of study enrollment or intended receipt of any investigational medicinal product at any time during study participation 5. Concurrent participation or intent to participate in another clinical trial or other study throughout the entire timeframe for this study. 6. Presence of severe malnutrition [weight-for- length/height z-score <-3SD median (per WHO published child growth standards)] – temporary exclusion if marginal and subsequently gains weight. 7. Presence of any clinically significant systemic disorder (cardiovascular, respiratory, hepatic, renal, gastrointestinal, hematological, endocrine, dermatological, neurological, cancer or autoimmune disease) as determined by medical history and/or physical examination that could compromise the subject’s health, is likely to result in nonconformance to the protocol or is likely to interfere with the evaluation of safety or immunogenicity endpoints. 8. History or examination findings suggestive of a primary or secondary immunodeficiency or known maternal HIV infection 9. Household member (living under the same roof/in the same building rather than in the same compound) with a history indicating or suggestive of a primary or secondary immunodeficiency 10. Evidence of a clinically significant congenital or genetic defect as judged by the investigator 11. Known sensitivity or allergy to any components Infant: 1 Month-23 Month,Preschool Child: 2 Year-5 Year 18 Week(s) 5 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 17/08/2020 Medical Research Council Ethics Committee
Ethics Committee Address
Street address City Postal code Country
MRC Unit The Gambia at LSHTM Atlantic Boulevard, Fajara P. O. Box 273, Banjul The Gambia Banjul The Gambi Gambia
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Secondary Outcome Immunogenicity • To further evaluate the immune response across three lots of a single dose of nOPV2 in healthy infants in The Gambia (in terms of median and geometric mean Nab titers and seroprotection rate [SPR]) • To assess the combined immunogenicity of three lots of nOPV2 in healthy infants in The Gambia (in terms of SCR, SPR, and median and geometric mean of anti-type 2 polio Nab) • To evaluate the immune response following a second dose of nOPV2 in healthy infants in The Gambia (in terms of SCR, SPR, median and geometric mean Nab titers) • To evaluate the immune response following a first and second dose of nOPV2 in healthy young children in The Gambia (in terms of SCR, SPR, and median and geometric mean Nab titers) Viral Shedding • To evaluate the rate and duration of viral shedding following a single dose of nOPV2 Exploratory Objective: • To assess the magnitude of shed virus (among those identified as shedding post-vaccination) Day 29 and Day 57
Primary Outcome Safety: • Frequency of serious adverse events (SAEs) throughout the 3 months after the last dose of study vaccine • Frequency of solicited adverse events (AEs) during the 7 days post-vaccination (in young children and a subset of infants receiving 2 doses) • Frequency of unsolicited AEs through 28 days after the last dose of study vaccine Immunogenicity: • Proportion of infants with anti-polio Nab seroconversion 28 days following a single dose of nOPV2. Seroconversion is defined by minimum 4-fold increase in titer between baseline and 28 days post-vaccination among those initially seropositive, or seropositivity [anti-polio Nab titer ≥1:8] at 28 days among those initially seronegative. Day 29 and Day 57
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Medical Research Council at the London School of Hygiene and Tropical Medicine LSHTM in the Gambia Atlantic Boulevard, Fajara P. O. Box 273 Banjul The Gambi Gambia
FUNDING SOURCES
Name of source Street address City Postal code Country
Bill and Melinda Gates Foundation 440 5th Avenue N. Seattle, WA 98109 Mailing Address PO Box 23350 Seattle 98102 United States of America
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor PATH 2201 Westlake Avenue, Suite 200 Seattle, WA 98121, USA Seattle 98121 United States of America Charities/Societies/Foundation
COLLABORATORS
Name Street address City Postal code Country
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Ed Clarke ed.clarke@lshtm.ac.uk +2207039732 Atlantic Boulevard, Fajara P. O. Box 273
City Postal code Country Position/Affiliation
Banjul The Gambi Gambia Lead Vaccine Clinical Trials
Role Name Email Phone Street address
Scientific Enquiries Beatte Kampmann bkampmann@mrc.gm +2204495442 Atlantic Boulevard, PO Box 273
City Postal code Country Position/Affiliation
Banjul The Gambi Gambia Professor
Role Name Email Phone Street address
Public Enquiries Njilan Johnson Njilan.Johnson@lshtm.ac.uk +2204789330 Atlantic Boulevard, Fajara P. O. Box 273
City Postal code Country Position/Affiliation
Banjul The Gambi Gambia Project Director
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Study results will be made publicly available in compliance with the WHO mandated timeframe for public disclosure of results from clinical trials. Any publication, lecture, manuscripts of the findings of this study by any individual involved with the study will be governed by the procedure outlined in the Clinical Trial Agreement. The ICMJE authorship criteria will be strictly followed for publication of any manuscripts arising from this trial. Clinical Study Report,Informed Consent Form,Study Protocol Within 12 months. Within any presentation or publication, confidentiality of individual subjects will be maintained, with identification by subject code number and initials, if applicable. All bodies involved in the conduct of this trial, including MRCG and LSHTH, PATH and Bio Farma, will be specifically acknowledged in any external communication of the trial results irrespective of the medium used.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information