Randomized Controlled Trial
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 21, 2015; 21(23): 7305-7312
Published online Jun 21, 2015. doi: 10.3748/wjg.v21.i23.7305
Recombinant streptokinase vs hydrocortisone suppositories in acute hemorrhoids: A randomized controlled trial
Francisco Hernández-Bernal, Georgina Castellanos-Sierra, Carmen M Valenzuela-Silva, Karem M Catasús-Álvarez, Osmany Martínez-Serrano, Odalys C Lazo-Diago, Cimara H Bermúdez-Badell, José R Causa-García, Juan E Domínguez-Suárez, Pedro A López-Saura; THERESA-4 (Treatment of HEmorrhoids with REcombinant Streptokinase Application) Group of Investigators
Francisco Hernández-Bernal, Carmen M Valenzuela-Silva, Karem M Catasús-Álvarez, Odalys C Lazo-Diago, Cimara H Bermúdez-Badell, Pedro A López-Saura, Clinical Research Direction, Center for Genetic Engineering and Biotechnology, Havana 74110, Cuba
Georgina Castellanos-Sierra, Juan B. Zayas Hospital, Santiago de Cuba 90100, Cuba
Osmany Martínez-Serrano, Ernesto Guevara Hospital, Las Tunas 75100, Cuba
José R Causa-García, Celia Sánchez Hospital, Manzanillo, Granma 88000, Cuba
Juan E Domínguez-Suárez, Gustavo Aldereguía Hospital, Cienfuegos 55100, Cuba
Author contributions: Hernandez-Bernal F, Castellanos-Sierra G, Valenzuela-Silva CM and López-Saura PA conceptualized and designed this study; Castellanos-Sierra G, Martínez-Serrano O, Causa-García JR and Domínguez-Suárez JE performed the clinical investigations and recruited/treated the majority of included patients; Hernandez-Bernal F, Catasús-Álvarez KM, Lazo-Diago OC and Bermúdez-Badell CH took part in trial coordination and monitoring; Hernandez-Bernal F, Castellanos-Sierra G, Valenzuela-Silva CM, Catasús-Álvarez KM, Martínez-Serrano O, Lazo-Diago OC, Bermúdez-Badell CH, Causa-García JR and Domínguez-Suárez JE collected and managed the data; Valenzuela-Silva CM and López-Saura PA contributed to the statistical analyses; Hernandez-Bernal F, Castellanos-Sierra G, Valenzuela-Silva CM and López-Saura PA analyzed and interpreted the data; Hernandez-Bernal F and López-Saura PA drafted the manuscript and gave final approval for the version to be published.
Supported by Heber Biotec, Havana (for providing products and reagents) and the Ministry of Public Health of Cuba (for hospital facilities and general medical care of patients).
Ethics approval: The study was reviewed and approved by the Ethics Committees of the participating hospitals and by the Cuban Regulatory Authority.
Clinical trial registration: This study is registered at http://registroclinico.sld.cu/. Cuban Public Clinical Trial Registry (Primary Registry of WHO). The registration identification number is RPCEC00000122.
Informed consent: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest: Hernández-Bernal F, Valenzuela-Silva CM, Catasús-Álvarez KM, Lazo-Diago OC, Bermúdez-Badell CH and López-Saura PA are employees of the Center for Genetic Engineering and Biotechnology, Havana Network, where rSK is produced and the new formulation was developed. The remaining authors have no conflict of interests. No honoraria, consulting fees, or payments for seminar presentations, speeches, or appearances have been received by any of the authors.
Data sharing: Technical appendix, statistical code, and dataset available from the corresponding author at hernandez.bernal@cigb.edu.cu. Consent for data sharing was not obtained from participants, but the presented data are anonymized and risk of identification is null.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Francisco Hernández-Bernal, MD, MSc, Clinical Research Direction, Center for Genetic Engineering and Biotechnology, PO Box 6162, Havana 74110, Cuba. hernandez.bernal@cigb.edu.cu
Telephone: +53-7-2087421 Fax: +53-7-2736008
Received: November 12, 2014
Peer-review started: November 15, 2014
First decision: December 26, 2014
Revised: January 10, 2015
Accepted: January 21, 2015
Article in press: January 21, 2015
Published online: June 21, 2015

AIM: To compare the efficacy and safety of recombinant streptokinase (rSK) vs hydrocortisone acetate-based suppositories in acute hemorrhoidal disease.

METHODS: A multicenter (11 sites), randomized (1:1:1), open, controlled trial with parallel groups was performed. All participating patients gave their written, informed consent. After inclusion, patients with acute symptoms of hemorrhoids were centrally randomized to receive, as outpatients, by the rectal route, suppositories of rSK 200000 IU of one unit every 8 h (first 3 units) and afterwards every 12 h until 8 administrations were completed (schedule A), one unit every 8 h until 6 units were completed (schedule B), or 25 mg hydrocortisone acetate once every 8 h up to a maximum of 24 administrations. Evaluations were performed at 3, 5, and 10 d post-inclusion. The main end-point was the 5th-day response (disappearance of pain and bleeding, and ≥ 70% reduction of the lesion size). Time to response and need for thrombectomy were secondary efficacy variables. Adverse events were also evaluated.

RESULTS: Groups were homogeneous with regards to demographic and baseline characteristics. Fifth day complete response rates were 156/170 (91.8%; 95%CI: 87.3-96.2), 155/170 (91.2%; 95%CI: 86.6%-95.7%), and 46/170 (27.1%; 95%CI: 20.1%-34.0%) with rSK (schedule A and B) and hydrocortisone acetate suppositories, respectively. These 64.6% and 63.9% differences (95%CI: 56.7%-72.2% and 55.7%-72.0%) were highly significant (P < 0.001). This advantage was detected since the early 3rd day evaluation (68.8% and 64.1% vs 7.1% for the rSK and active control groups, respectively; P < 0.001) and was maintained even at the late 10th day assessment (97.1% and 93.5% vs 67.1% for rSK and hydrocortisone acetate, respectively; P < 0.001). Time to response was 3 d (95%CI: 2.9-3.1) for both rSK groups and 10 d (95%CI: 9.3-10.7) in the hydrocortisone acetate group. This difference was highly significant (P < 0.001). All subgroup stratified analyses (with or without thrombosis and hemorrhoid classification) showed a statistically significant advantage for the rSK groups. Thrombectomy was necessary in 4/251 and 14/133 patients with baseline thrombosis in the rSK and hydrocortisone acetate groups, respectively (P < 0.001). There were no adverse events attributable to the experimental treatment.

CONCLUSION: rSK suppositories showed a significant advantage over a widely-used over-the-counter hydrocortisone acetate preparation for the treatment of acute hemorrhoidal illness, as well as having an adequate safety profile.

Keywords: Streptokinase, Suppository, Hydrocortisone acetate, Thrombolysis, Hemorrhoids, Randomized clinical trial

Core tip: Medical treatments for acute hemorrhoidal disease very seldom come from randomized, controlled clinical trials. The paper describes recombinant streptokinase suppositories, a candidate to a new therapeutic alternative based on thrombolysis. The results show a significant efficacy advantage with respect to hydrocortisone acetate, a widely-used, over-the-counter product.