| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Healthy volunteers (chronic obstructive pulmonary disorder [COPD])) |
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| E.1.1.1 | Medical condition in easily understood language |
| COPD is a lung disease that makes it hard to breathe. It is caused by damage to the lungs over many years, usually from smoking |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10009033 |
| E.1.2 | Term | Chronic obstructive pulmonary disease |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To demonstrate the non-inferiority (NI) of the humoral immune response 1 month after Dose 2 of GSK Biologicals' NTHi-Mcat investigational vaccine when administered 1 or 3 or 6 months after Shingrix vaccine versus the humoral immune response 1 month after Dose 2 of GSK Biologicals' NTHi-Mcat investigational vaccine alone. A modified primary objective will be applicable if the sample size for the per-protocol set is not reached for the Sh_NTHi-Mcat_6 or the Sh_NTHi-Mcat_6 and _3 groups. If the per protocol defined sample size is not reached for the Sh_NTHi-Mcat_6 and _3 groups, the NI testing will be performed on the Sh-NTHI-Mcat_1 group.
Criterion: NI will be demonstrated if the lower limit (LL) of the 2-sided 95% CI of the geometric mean concentration (GMC) ratio (Sh_NTHi-Mcat/NTHi-Mcat) is above a limit of 0.667 for all anti-Protein D (PD), anti-Protein E (PE), anti-type IV pili subunit (PilA), anti- ubiquitous surface protein A2 of Moraxella catarrhalis (Us-pA2). |
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and reactogenicity profile of GSK Biologicals' NTHi-Mcat investigational vaccine when administered 1 or 3 or 6 months after Shingrix vaccine or when administered alone.
• To describe the humoral immune response of GSK Biologicals' NTHi-Mcat investigational vaccine when administered 1 or 3 or 6 months after Shingrix vaccine or when administered alone.
• To describe the cell-mediated immune (CMI) response of GSK Biologicals’ NTHi-Mcat investigational vaccine when administered 1 or 3 or 6 months after Shingrix vaccine or when NTHi-Mcat is administered alone, in the CMI response subcohort. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol (e.g. completion of the diary cards, return for follow-up visits).
• Written informed consent obtained from the subject prior to performance of any study specific procedure.
• A male or female between, and including, 50 years and 80 years of age at the time of the first vaccination.
• Healthy subjects as established by medical history and clinical examination before entering into the study.
• Current or former smoker with a cigarette smoking history ≥10 pack-years.
• Female subjects of non-childbearing potential may be enrolled in the study. Non-childbearing potential is defined as pre-menarche, current bilateral tubal ligation or occlu-sion, hysterectomy, bilateral ovariectomy or post-menopause.
• Female subjects of childbearing potential may be enrolled in the study, if the subject: has practiced adequate contraception for 30 days prior to vaccination, and; has a negative pregnancy test on the day of vaccination, and; has agreed to continue adequate contraception during the entire treatment period and for 2 months after completion of the vaccination series. |
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| E.4 | Principal exclusion criteria |
Medical conditions
• Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required).
• History of potential immune-mediated disease (pIMD).
Note: If the subject has any condition on the list of pIMDs specified in the protocol, they must be excluded unless the aetiology is clearly documented to be non-immune mediated. The investigator will exercise his/her medical and scientific judgement in deciding whether other diseases have an autoimmune origin and thus meet the exclusion criteria.
• Diagnosis of COPD regardless of severity.
• History of allergic disease or reactions likely to be exacerbated by any component of the vaccines. Additionally, consider allergic reactions to other material or equipment related to study participation (such as materials that may possibly contain latex –gloves, syringes, etc).
• Has significant disease (including significant psychological disorders), in the opinion of the investigator, likely to interfere with the study and/or likely to cause death within the study duration.
• History of or current condition preventing intramuscular injection as bleeding or coagulation disorder.
• Malignancies within previous 5 years (excluding non-melanoma skin cancer) or lymphoproliferative disorders.
Prior/concomitant therapy
• Use of any investigational or non-registered product (drug or vaccine) other than the study vaccines during the period starting 30 days before the first dose of study vaccine (Day -29 to Day 1), or planned use during the study period.
• Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting 30 days before the first dose and ending 30 days after the last dose of vaccine administration, with the exception of non-MF59 adjuvanted influenza vaccines and pneumococcal vaccines which may be administered ≥15 days preceding or following any study vaccine dose.
Note: For M59 adjuvanted flu vaccine and for any vaccine containing novel adjuvant refer to exclusion criteria below.
• Planned administration/administration of a vaccine adjuvanted with the following adjuvants AS01, AS02, AS03, AS04 and MF59 in the period starting 6 months before the first dose of study vaccine, and ending at the second blood draw (i.e. approximately 1 month after the administration of the last dose of NTHi-Mcat vaccine). The following non-exhaustive list should be considered as criteria for exclusion: Prepandrix, Adjupanrix, Shingrix, Fendrix, Cervarix, FluAd, Chiromas, Gripguard.
• Previous vaccination with any vaccine containing NTHi and/or Mcat antigens; .
• Previous vaccination with Shingrix; (either registered product or participation in a previous vaccine study).
• Previous vaccination with HZ live-attenuated vaccine (ZVL)) (either registered product or participation in a previous vaccine study) within the 2 months of the first study visit (Day 1).
• Administration of long-acting immune-modifying drugs at any time during the study period (e.g. infliximab).
• Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs during the period starting 6 months prior to the first vaccine dose, and ending at the second blood draw. (i.e. approximately 1 month after the administration of the last dose of NTHi-Mcat vaccine). For corticosteroids, this will mean prednisone ≥5 mg/day (for adult subjects), or equivalent. Only topical steroids are allowed.
• Administration of immunoglobulins and/or any blood products or plasma derivatives during the period starting 3 months before the first dose of study vaccine or planned administration starting from Day 1 and ending at the second blood draw (i.e. approximately 1 month after the planned administration of the second dose of NTHi-Mcat vaccine).
Prior/concurrent clinical study experience
• Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational vaccine/product (drug or medical device).
Other exclusions:
• Pregnant or lactating female,
• Female planning to become pregnant or planning to discontinue contraceptive precautions,
• Current alcoholism and/or drug abuse,
• Any other clinical condition that, in the opinion of the investigator, might pose additional risk to the subject due to participation in the study
• Any study personnel or immediate dependents, family, or household member. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Anti-PD, anti-PE, anti-PilA and anti-UspA2 antibody concentrations in terms of Geometric Mean Concentrations (GMCs), one-month post Dose-2 of NTHi-Mcat vaccine.
Antibody concentrations are measured by ELISA (Enzyme-linked immunosorbent assay) and expressed as GMCs in ELISA units per milliliter (EU/mL). Cut-off value for the assay is 153, 25 ,16 and 38 EU/mL for anti-PD, anti-PE, anti-PilA and anti-UspA2 antibodies respectively.
If per protocol set (PPS) sample size is not met in Sh_NTHi_Mcat_6 group then timeframe will be adapted as follows: At 1 month after Dose 2 of NTHi-Mcat vaccine (Day 181, 241 in Sh_NTHi-Mcat_1 and Sh_NTHi-Mcat_3 group respectively and Day 91 in NTHi-Mcat group)
If PPS sample size is not met in Sh_NTHi_Mcat_6 or in Sh_NTHi-Mcat_6 and Sh_NTHi-Mcat_3 groups then timeframe will be adapted as follows: At 1 month after Dose 2 of NTHi-Mcat vaccine (Day 181 in Sh_NTHi-Mcat_1 group and Day 91 in NTHi-Mcat group) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At 1 month after Dose 2 of NTHi-Mcat vaccine (Day 181 [Sh_NTHi-Mcat_1], Day 241 [Sh_NTHi-Mcat_3] and Day 331 [Sh_NTHi-Mcat_6], and Day 91 [NTHi-Mcat]) |
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| E.5.2 | Secondary end point(s) |
Immunogenicity
1. Anti–PD, anti-PE, anti-PilA, anti-UspA2 antibody concentrations in terms of GMCs, before the first dose of NTHi-Mcat vaccine.
Note: GMCs and their 95% CI for each of the antibodies, as measured by ELISA, are calculated (the GMCs are computed by taking the anti-log of the mean of the log concentration transformations) before the first dose of NTHi-Mcat vaccine
2. Percentage of seropositive subjects for anti-PD, anti-PE, anti-PilA, anti-UspA2 antibodies before first NTHi-Mcat vaccine.
3. Percentage of subjects seropositive for anti-PD, anti-PE, anti-PilA, anti-UspA2 antibodies, at 1 month post Dose-2 of NTHi-Mcat vaccine.
Note: A seropositive subject is defined as a subject whose anti-PD, anti-PE, anti-PilA and anti-UspA2 antibody concentrations are greater than or equal to the assay cut-off value. Seropositivity rates with 95% CI are defined using the assay lower limit of quantification (LLOQ). Seropositivity rates are calculated before the first dose of NTHi-Mcat Vaccine and at 1 month post Dose-2 of NTHi-Mcat vaccine
4. Frequency of specific Cluster of Differentiation 4 (CD4+) T-cells against NTHi and Mcat antigens for evaluation of cell-mediated immune (CMI) response, before the first dose of NTHi-Mcat vaccine.
5. Frequency of CD4+ T-cells against NTHi and Mcat antigens for evaluation of CMI response, at 1-month post Dose 2 of NTHi-Mcat vaccine.
Note: Frequency of specific CD4+ T-cells is measured by flow cytome-try intracellular cytokine staining (ICS) expressing at least 2 different cytokines/activation markers among CD40 Ligand (CD40L), interleukin (IL)-2, IL-13, IL-17, tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ), upon in vitro stimulation.
Safety
6. Percentage of subjects with reported solicited local adverse event (AE)
Note: The percentage of subjects with at least 1 local solicited AE, regardless of intensity, during the 7-day follow-up period after each vaccination, are reported after each vaccination by study group. Assessed local symptoms are pain, redness and swelling. Any local injection site redness/swelling is scored as follows: diameter ≥20 millimeters.
7. Percentage of subjects with reported solicited general AE
Note: The percentage of subjects with at least 1 general solicited AE, regardless of intensity, during the 7-day follow-up period after each vaccination, are reported by study group. Assessed solicited general symptoms are Fatigue, Gastrointestinal symptoms (nausea, vomiting, diarrhoea and/or abdominal pain), Myalgia, Chills and Fever (oral cavity or axillary route - temperature equal or higher than [≥] 37.5 degrees Celsius [°C]).
8. Percentage of subjects with any unsolicited AE
Note: An unsolicited adverse event is an adverse event that was not solicited using a Subject Diary and that was spontaneously com-municated by a subject who has signed the informed consent. The percentage of subjects with at least one unsolicited AE, regardless of intensity or relationship to vaccination, during the 30 day follow-up period after any study vaccination are reported for each group and by MedDRA Preferred Term. Any ‘solicited’ symptom with onset outside the specified period of follow-up for solicited symptoms will be reported as an unsolicited adverse event.
9. Percentage of subjects with any serious adverse event (SAE) during Epoch 001
10. Percentage of subjects with any SAE during Epoch 002
Note: The percentage of subjects with at least one SAE, regardless of intensity or relationship to vaccination are reported for each group and by MedDRA Preferred Term. An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of hospitalization, results in disability/incapacity in a subject or is a congenital anomaly/birth defect in the offspring of a study subject. AE(s) considered as SAE(s) also include invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, as per the medical or scientific judgement of the physician.
11. Percentage of subjects with any potential immune-mediated diseases (pIMDs) (see note) during Epoch 001.
12. Percentage of subjects with any pIMDs (see note) during Epoch 002
Note: Potential immune-mediated diseases (pIMDs) are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Immunogenicity
1, 2, 4: Before Dose 1 of NTHi-Mcat vaccine: Day 91 (Sh_NTHi-Mcat_1), 151 (Sh_NTHi-Mcat_3), & 241 (Sh_NTHi-Mcat_6) & Day 1 (NTHi-Mcat)
3, 5: 1 month post-Dose 2 NTHi-Mcat vaccine: Day 181 (Sh_NTHi-Mcat_1), 241 (Sh_NTHi-Mcat_3), & 331 (Sh_NTHi-Mcat_6) & Day 91 (NTHi-Mcat)
Safety
6,7 (solicited AEs): 7-days after each NTHi-Mcat vaccine (Day 98 & 158 [Sh_NTHi-Mcat_1], Day 158 & 218 [Sh_NTHi-Mcat_3], & Day 248 & 308 [Sh_NTHi-Mcat_6]), & Day 8 & 68 [NTHi-Mcat])
8 (unsolicited AEs): 30-days after each NTHi-Mcat vaccination (Day 121 & 181 [Sh_NTHi-Mcat_1], Day 181 & 241 [Sh_NTHi-Mcat_3], & Day 271 & 331 [Sh_NTHi-Mcat_6], & Day 31 & 91 [NTHi-Mcat])
9, 10 (SAEs): Day 1 to Day 331 & Day 331 to Day 661
11, 12 (pIMDs): Day 1 to Day 331 & Day 331 to Day 661
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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