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. 2022 Jan 14;17(1):e0262273. doi: 10.1371/journal.pone.0262273

Table 1. Study and participants’ characteristics in the included RCTs.

N Author (year) Countries or regions Population: hemophilia type, age and sex Factor activity level** Product: type of clotting factor concentrates and half-life (hours) Control (n) Intervention (n) Follow-up Fun-ding
Episodic treatment compared with prophylaxis (at low, intermediate, and high doses)
1 Verma (2016) India

  • Hemophilia A

  • Age range: 1 to 10 yr (mean: 6.11 yr)

  • Sex: not mentioned

 < 1% FVIII concentrate (Hemofil M)

  • Plasma-derived, mAb-purified

  • 15 h

 Episodic (n = 10)

  1. 25 IU/kg or more as early as possible after the joint bleed,

  2. 25 IU/kg every 12–24 h until resolution

 Low-dose prophylaxis (n = 11)

  • Weekly dose: 20 IU/kg (10 IU/kg twice a week)

 Median: 0.96 yr Self-funded
2 Chozie (2019) Indonesia

  • Hemophilia A

  • Age range: 4 to 18 yr (mean: 11.95 yr)

  • Sex: not mentioned

 < 1% FVIII concentrate (Koate-DVI)

  • Plasma-derived, chromatography purified

  • 16 h

 Episodic (n = 25)

  • Not specified

 Low-dose prophylaxis (n = 25)

  • Weekly dose: 20 IU/kg (10 IU/kg twice a week)

 Mean: 1 yr Grifols
3 Manco-Johnson (2007) and Hacker (2007) United States

  • Hemophilia A

  • Age range: 1 to 2.5 yr (mean: 1.6 yr)

  • Sex: 100% males

 ≤ 2% FVIII concentrate (Kogenate or Kogenate FS)

  • Recombinant

  • 11 to 15 h

 Episodic (n = 33)

  1. 40 IU/kg at the time of joint hemorrhage.

  2. 20 IU at 24 hours and 72 hours after the first dose

  3. 20 IU/kg every second day, until 4 weeks.

 Intermediate-dose prophylaxis (n = 32)

  • Weekly dose: 75 IU/kg (25 IU/kg every second day)

 Mean: 4.08 yr CDC, NIH, Bayer
4 Gringeri (2011) Italy

  • Hemophilia A

  • Age range: 1 to 7 yr (mean: 4.10 yr)

  • Sex: not mentioned

 < 1% FVIII concentrate (Recombinate® until 2003 / Advate® since 2004)

  • Both were recombinant

  • Recombinate: 15 h / Advate: 9 to 12 h

  • 1° generation / 3° generation

 Episodic (n = 19)

  1. 25 IU/kg or more, possibly within 6 h from the bleeding,

  2. Repeated every 12–24 h until complete resolution

 Intermediate-dose prophylaxis (n = 21)

  • Weekly dose: 75 IU/kg (25 IU/kg three times a week)

 Median: 6.88 yr Baxter
5 Manco-Johnson (2014) and Manco-Johnson (2017) United States, Bulgaria, Romania and Argentina

  • Hemophilia A

  • Age range: 12 to 50 yr (mean: 29 yr)

  • Sex: 100% males

 < 1% FVIII concentrate (Kogenate FS)

  • Recombinant

  • 11 to 15 h

 Episodic (n = 42)

  • Not specified

 Intermediate-dose prophylaxis (n = 41)

  • Weekly dose: 75 IU/kg (25 IU/kg three times a week)

 3 yr Bayer
6 Kavakli (2015) Europe, South Africa, North America, South America, and Asia

  • Hemophilia A

  • Age range: 12 to 65 yr (mean: 29.6 yr)

  • Sex: 100% males

 < 1% FVIII concentrate (BAY 81–8973, Kovaltry)

  • Recombinant

  • 12 to 14 h

 Episodic (n = 21)

  • Dependent on the location and severity of the bleed

 Intermediate-dose prophylaxis (n = 28)

  • Weekly dose: 40 to 60 IU/kg (20–30 IU/kg twice a week)

 1 yr Bayer
High-dose prophylaxis (n = 31)

  • Weekly dose: 90 to 120 IU/kg (30–40 IU/kg three times a week)

Studies that compared two different prophylactic factors
1 Powell (2012) United States, Israel, Poland, Italy, Austria, and Denmark

  • Hemophilia A

  • Age range: 12 to 70 yr (mean: 33.6 yr)

  • Sex: 100% males

 < 1% Intervention groupKogenate FS reconstituted with a pegylated liposome solvent (BAY 79–4980)

  • Recombinant

  • 11 to 15 h


Control group rFVIII-FS (Kogenate FS)


  • Recombinant

  • 11 to 15 h

 rFVIII-FS (n = 68)

  • Weekly dose: 75 IU/kg (25 IU/kg three times a week)

 BAY 79–4980 (n = 63)

  • Weekly dose: 35 IU/kg (35 IU/kg once a week)

 Median: 0.96 yr Bayer
Studies that assessed the pharmacokinetic prophylaxis
1 Valentino (2012) United States and Europe

  • Hemophilia A

  • Age range: 7 to 65 yr (median: 27.5 yr)

  • Sex: 100% males

 ≤ 2% FVIII concentrate (Advate)

  • Recombinant

  • 9 to 12 h

 Intermediate- to high-dose prophylaxis (n = 32)

  • Weekly dose: 70 to 140 IU/kg (20–40 IU/kg every 48 ± 6 h)

 PK-prophylaxis (n = 34)

  • Weekly dose: 46.7 to 186.7 IU/kg (20–80 IU/kg every 72 ±6 h)

 Mean: 0.96 yr Baxter
Studies in which the groups received the same weekly doses but with different frequency
1 Valentino (2014) United States, Canada, and Europe

  • Hemophilia B

  • Age range: 6 to 65 yr (mean: 28.4 yr)

  • Sex: 100% males

 ≤ 2% FIX concentrate (BeneFIX)

  • Recombinant

  • 16 to 19 h

 High-dose prophylaxis (n = 22)

  • Weekly dose: 100 IU/kg (100 IU/kg once a week)

 High-dose prophylaxis (n = 25)

  • Weekly dose: 100 IU/kg (50 IU/kg twice a week)

 32 weeks (0.62 yr) Pfizer

yr: years; IQR: Interquartile range; SD: Standard deviation; mAb-purified: monoclonal antibody-purified; rFVIII-FS: Sucrose-formulated rFVIII.

*All studies excluded patients with inhibitors.

**Factor VIII for all studies performed in patients with haemophilia A, or factor IX for the study performed in patients with haemophilia B.