Koutsky & | Harper | Villa | FUTURE I | FUTURE II | PATRICIA | Muñoz et al [18] | ||||||||
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Phase | III | III | II | III | III | III | III | |||||||
No. of study sites | 16 | 32 | 5 | 62 | 90 | 135 | 38 | |||||||
Countries included | 1 | 3 | 5 | 16 | 13 | 14 | 7 | |||||||
Year of study enrollment | 10/1998-11/1999 | 11/2003-07/2004 | Not reported | 01/2002-03/2003 | 06/2002-05/2003 | 05/2004-06/2005 | 06/2004-04/2005 | |||||||
Funding source | Merck | GlaxoSmithKline | Merck | Merck | Merck | GlaxoSmithKline | Merck | |||||||
Inclusion Criteria | ||||||||||||||
Age | 16-25 | 15-25 | 16-23 | 16-24 | 15-26 | 15-25 | 24-45 | |||||||
Lifetime no. of sexual partners | ≤ 5 | ≤ 6 | ≤ 4 | ≤ 4 | ≤ 4 | ≤ 6 | No restriction | |||||||
Exclusion Criteria | Pregnancy, history of abnormal Pap smear | History of abnormal Pap smear, or ablative or excisional treatment of cervix; ongoing treatment for external condylomata; seropositive for HPV 16 or 18; DNA positive for any of 14 HR HPV in past 90 days | Pregnancy, history of abnormal Pap smear | Pregnancy, history of abnormal Pap smear or genital warts | Pregnancy, history of abnormal Pap smear | History of colposcopy, pregnancy, breastfeeding, autoimmune diseases or immunodeficiency | Pregnancy, history of genital warts, present or past cervical disease, immunocompromised | |||||||
Intervention & Comparator | ||||||||||||||
Vaccine component | HPV 16 VLPs | HPV 16, 18 VLPs | HPV 6, 11, 16, 18 VLPs | HPV 6, 11, 16, 18 VLPs | HPV 6, 11, 16, 18 VLPs | HPV 16, 18 VLPs | HPV 6, 11, 16, 18 VLPs | |||||||
VLP amount (μg) | 40 | 20/20 | 20/40/40/20 | 20/40/40/20 | 20/40/40/20 | 20/20 | 20/40/40/20 | |||||||
Vaccine adjuvant | 225 μg AAHS | AS04 (500 μg/50 μg) | 225 μg AAHS | 225 μg AAHS | 225 μg AAHS | AS04 (500 μg/50 μg) | 225 μg AAHS | |||||||
Comparator | Placebo | Placebo | Placebo | * Placebo/Placebo+Hepatitis B vaccine | Placebo | Hepatitis A vaccine | Placebo | |||||||
Comparator adjuvant | 225 μg AAHS | 500 μg aluminium hydroxide | 225 or 450 μg AAHS | 225 μg AAHS | 225 μg AAHS | 500 μg aluminium hydroxide | 225 μg AAHS | |||||||
Administration schedule | month 0, 2, 6 | month 0, 1, 6 | months 0, 2, 6 | month 0, 2, 6 | month 0, 2, 6 | month 0, 1, 6 | month 0, 2, 6 | |||||||
Clinical Protocol | ||||||||||||||
Frequency of HPV DNA test | 6 month interval | 6 month interval | 6 month interval | 6 month interval | 6 month interval | 6 month interval | 6 month interval | |||||||
Frequency of cytology test | 6 month interval | 6 month interval | 6 month interval | 6 month interval | 12 month interval | 12 month interval | 6 month interval | |||||||
Length of trial (months) | 41.0 | Initial trial: 27 Follow-up study: 53 | Initial trial: 36 Follow-up study: 60 | 36.0 (mean) | 36.0 (mean) | 39.4 (mean) | 26.4 (mean) | |||||||
Endpoints | ||||||||||||||
Primary | Persistent HPV 16 infection | Incidence infection with HPV 16, and/or 18. | Combined incidence of HPV 6, 11, 16 and/or 18-associated 6-month persistent infection, CIN1-3, AIS, VIN1-3, VaIN1-3, external genital warts and cervical, vulvar or vaginal cancer. | Incidence of HPV 6, 11, 16, and/or 18-associated genital warts, CIN1-3, VIN1-3, VaIN1-3, AIS, and cervical, vulvar or vaginal cancer | HPV 16 and/or 18-associated CIN 2-3, AIS and cervical cancer | HPV 16/18-associated CIN2+ | Combined incidence of 6-month persistent infection, CIN1-3, VIN1-3, VaIN1-3, AIS, cervical, vulvar or vaginal cancer, and genital warts associated with HPV 6, 11, 16 or 18, or with HPV 16 or 18 alone. | |||||||
Secondary | Transient or persistent HPV 16 infection | Persistent infection with HPV 16, 18 or 16/18; HPV 16/18-associated LSIL, HSIL, CIN1-3 and cancer | Combined incidence of HPV 6, 11, 16 and/or 18-associated CIN1-3, AIS and cancer; Persistent infection, CIN1-3 and AIS associated with HPV 31, 33, 45, 52, 58. | Persistent infection, CIN1-3 and AIS associated with HPV 31, 33, 45, 52, 58 | Persistent infection with HPV 16, 18 or other oncogenic types; HPV 16/18-associated CIN1+; immunogenicity and safety | Combined incidence of 6-month persistent infection, CIN1-3, VIN1-3, VaIN1-3, AIS, cervical, vulvar or vaginal cancer, or genital warts associated with HPV 6 or 11 | ||||||||
Populations for Efficacy Analysis | ||||||||||||||
Per-protocol population (PPP) | All subjects that received 3 doses of vaccine/placebo; DNA negative for HPV 16 in cervical swab and biopsy from day 1 to month 7; seronegative for HPV 16 on day 1; had no protocol violation; had a month 7 visit within 14-72 days after the third vaccination | All subjects that received 3 doses of vaccine/placebo; DNA negative for 14 HR HPV on day 1; cytologically negative and seronegative for HPV 16 and 18 on day 1; had no protocol violation | All subjects that received 3 doses of vaccine/placebo within a year; seronegative and DNA negative for HPV 6, 11, 16 or 18 on day 1; remained DNA negative for the same HPV type(s) through month 7; had no protocol violation | All subjects that received 3 doses of vaccine/placebo within a year; seronegative and DNA negative for HPV 6, 11, 16 or 18 on day 1; remained DNA negative for the same HPV type(s) through month 7; had no protocol violation.† | All subjects that received 3 doses of vaccine/placebo within a year; seronegative and DNA negative for HPV 16 or 18 on day 1; remained DNA negative for the same HPV type(s) through month 7; had no protocol violation.† | All subjects that received 3 doses of vaccine/placebo; seronegative to HPV 16 or 18 on day 1; DNA negative to HPV 16 or 18 on day1 and month 6; had normal or low-grade cytology at baseline, had no protocol violation | All subjects that received 3 doses of vaccine/placebo within a year; seronegative and DNA negative in cervicovaginal swab and/or biopsy samples for HPV 6, 11, 16 or 18 on day 1; remained DNA negative to the same HPV type(s) through month 7; had no protocol violation; had one or more follow-up visits after month 7 | |||||||
Intention-to-treat (ITT)/Modified Intention-to-treat (MITT) population | MITT2: All subjects that received ≥1 dose of vaccine/placebo. | ITT: All subjects that received ≥1 dose of vaccine/placebo; DNA negative for 14 HR HPV on day 1; had data available for outcome measurement. | MITT: All subjects that received ≥1 dose of vaccine/placebo; seronegative and DNA negative to HPV 6, 11, 16 or 18 on day 1. | ITT: All subjects that had undergone randomization, regardless of their baseline HPV status or evidence of HPV-associated anogenital disease. | ITT: All subjects that had undergone randomization, regardless of their baseline HPV status or evidence of cervical neoplasia | ITT: All subjects that received ≥1 dose of vaccine/placebo; DNA negative to HPV 16 or 18 on day 1; had data available for outcome measurement. | ITT: All subjects that received ≥1 dose of vaccine/placebo; had one or more follow-up visits after day1. | |||||||
Methodological Quality | ||||||||||||||
Allocation concealment | Adequate | Adequate | Adequate | Adequate | Adequate | Adequate | Adequate | |||||||
Blinding | Adequate | Adequate | Adequate | Adequate | Adequate | Adequate | Adequate | |||||||
Dropout/loss-to-follow-up reported | Yes | Yes | Yes | Yes | Yes | Yes | Yes | |||||||
Expected efficacy (1-RR) | 0.75 | 0.70 | 0.80 | 0.80 | 0.80-0.90 | 0.85 | 0.80 | |||||||
Sample size calculation performed | Yes | Yes | Yes | Yes | Yes | Yes | Yes | |||||||
α = 0.05 (one-sided) | β = 0.10 | α = 0.05 (two-sided) | β = 0.20 | α = 0.05 (two-sided) | β = 0.10 | α = 0.0125 (one-sided) | β = 0.09 | α = 0.02055 (one-sided) | β = 0.10 | α = 0.05 (two-sided) | β = 0.06 | -- | β = 0.13 |