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Table 1 Characteristics of randomized controlled trials included in the review.

From: Efficacy and Safety of Prophylactic Vaccines against Cervical HPV Infection and Diseases among Women: A Systematic Review & Meta-Analysis

  Koutsky & Mao et al[28, 29] Harper et al [8, 9] Villa et al [23, 30] FUTURE I [17, 31, 32] FUTURE II [25, 31, 32] PATRICIA [16, 33] Muñoz et al [18]
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
  1. HR HPV: High-risk HPV includes HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68; CIN: Cervical intraepithelial neoplasia; AIS: Adenocarcinoma in situ; CIN1+: Cervical intraepithelial neoplasia grade 1 or worse, including CIN1-3, AIS and cervical cancer. CIN2+: Cervical intraepithelial neoplasia grade 2 or worse, including CIN2-3, AIS and cervical cancer; LSIL: Low-grade intraepithelial lesion; HSIL: High-grade intraepithelial lesion; VIN: Vulvar intraepithelial neoplasia; VaIN: Vaginal intraepithelial neoplasia. VLPs: Virus-like particles; AAHS: Amorphous aluminium hydroxyphosphate sulphate. AS04: 500 μg aluminum hydroxide and 50 μg 3-O-desacyl-4'-monophosphoryl lipid A; RR: Risk ratio, the ratio of event rates of vaccine and control group.
  2. * A subset of 466 subjects in the treatment arm received quadrivalent vaccine and Hepatitis B vaccine, and 467 subjects in control arm received placebo and Hepatitis B vaccine.
  3. † Per-protocol population for evaluation of cross-protection included subjects who received ≥1 vaccination and, at enrollment were seronegative and DNA negative for each of vaccine HPV types (6, 11, 16, and 18); were DNA negative for each of 10 non-vaccine types (31, 33, 35, 39, 45, 51, 52, 56, 58, and 59); and had a normal Pap test result.