Clindamycin Once a Day in Septic Abortion

Septic Abortion Clinical Trial

— CLINDA-PRO  

Official title:

A Randomized Clinical Trial Between Clindamycin Once and Thrice a Day in Septic Abortion.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02309346
• Other study ID #: 14-0328
• Status: Recruiting
• Phase: Phase 4
• Start date: December 31, 2014
• Est. completion date: December 2019

Study information

• Verified date: January 2018
• Source: Hospital de Clinicas de Porto Alegre
• Contact: Daniel M da Silva, Phar
• Phone: +555133597542
• Email: danielmsilva[@]hcpa.edu.br
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Septic abortion is a serious condition. Women with septic abortion are treated with clindamycin plus gentamicin using divided doses, i.e., thrice a day.

The objective of this study is to compare the rates of cure between once or thrice a day use of clindamycin with gentamicin in cases of septic abortion.

Description:

Obstetric infections are very common, especially in developing countries, as a consequence of the practice of unsafe abortion. In these countries, an estimated five million women each year are hospitalized due to complications from induced abortions, which equates to a rate of 5-7 per thousand women.

Abortion remains a leading cause of maternal death in developing countries. According to the World Health Organization, it is estimated that 1 in 8 maternal deaths occur from complications of illegal abortion. Septic abortions play an important role in the maternal morbidity and mortality. The diagnosis of septic abortion should be considered when a woman of reproductive age presents with menstrual delay, vaginal bleeding accompanied by abdominal pain and fever.

In 1989, Plaisance et al. demonstrated that Clindamycin, an antibiotic used for septic abortion, could be prescribed at a dose of 12/12 hours, and bacterial inhibitory serum levels were similar to those in divided doses 6/6 hours. In 2003, Livingston et al. published the results of gentamicin and clindamycin combined in a single daily dose for cases of post-cesarean endometritis. Administration of clindamycin differed by being in a dose of 2700mg daily dose of different fractional 6/6 hours, or 8/8 hours, and the cure rates were 82% (45 of 56 cases successes) in a single daily dose (13). The etiology of postpartum endometritis is similar to that in infected abortion (14, 15), but little information exists regarding the use of single daily dose in this disease.

A retrospective study recently conducted by our group showed that patients with infected abortion treated with Clindamycin single dose achieved cure rates of 98% (95% CI - 95 to 99%), suggesting an equivalence between a single daily dose and treatment conventional three daily doses.

OBJECTIVES The objective of this study is to verify the equivalence of using Clindamycin once a day versus 3 times daily in the rates of cure of septic abortion.

Hypotheses H0: Ps> Pn+2 The percentage of clinical cure with standard treatment (Ps) is greater than the rate of cure of alternative treatment + 2%.

Ha: Ps - 2% ≤ Pn The percentage of clinical cure with traditional treatment (Ps) minus 2% is less than or equal to the percentage of cure alternative treatment (Pn).

Variables

1. Standard treatment (Clindamycin 3x daily)

2. Alternative treatment (1x daily Clindamycin)

3. Clinical improvement (present or absent), defined as absence of fever (≤37.7 ° C), normal WBC (≤12.000 total leukocytes), eating and walking without difficulty, as already described in the literature.

Materials and methods Design Randomized, prospective, double-blind study with two arms that follow the parameters of the CONSORT (17).

Geographic and temporal limitations The study will be conducted in patients attending the emergency unit at HCPA. A period of 24 months for data collection (about 4 patients per month), it will be necessary to reach sample size.

Inclusion criteria

All patients who come to emergency unit at HCPA with clinical diagnosis of septic abortion and will be treated with Clindamycin will be invited. The diagnosis of infected abortion is the same as used previously described by our group (9). Briefly, the presence of one of the criteria below in a < 20 weeks gestation, associated with a suspected ovular infection:

1. History of intrauterine manipulation with contaminated objects.

2. Vaginal discharge with foul odor.

3. Presence of pus flowing through the cervix.

4. Signs of peritoneal irritation.

5. leukocytosis (> 14,000 leukocytes / ml).

6. Warm Extremities, thready pulse and tachycardia (HR> 110 bpm)

7. Cyanosis and / or paleness

8. Tachypnea (MR> 30mrpm)

9. hypotension (Systolic Blood Pressure <90 mmHg)

10. Oliguria

11. Hyperthermia (≥ 37.8 ° C) Exclusion criteria

Will be excluded all patients who:

1. Do not wish to participate in the project.

2. They used antibiotics prior to hospitalization (1 week period).

3. Being allergic to clindamycin or gentamicin. Execution Patients eligible for the study will be invited to participate in the study at hospital admission for uterine curettage. After reading and signing the informed consent, patients will answer a standardized interview and after the interview, she will be randomized.

Randomization Subjects will be randomly allocated to treatment with clindamycin 3 times a day, or once a day; random sequence will be generated by a computer grouped into blocks of 4 treatments. The randomization sequence will be obtained from sequential sealed envelope that will be in possession of the pharmacy emergency service HCPA. Researcher will not have access to the following treatment sequence. The Pharmacy Service will prepare the medication that will be part of routine emergency Gynecological Unit.

Patients and researchers will be blind to treatment allocation; saline infusion will be given in the place of clindamycin to keep patients blind to treatment arm.

Treatment

The regimen will consist of:

Standard treatment (Ps.): Clindamycin (900mg intravenously 8/8 hours diluted in 250 ml saline 0.9% solution (SF). The first vial of SF will contain 240 mg of gentamicin.

Alternative treatment (Pn): Clindamycin (2700mg) + gentamicin (240 mg) diluted in 250 ml of 0.9% saline. Two additional vials of SF 0.9% will be infused every 8 h as placebo.

The treatment will be continued up to 48 hours of good clinical condition, defined as absence of fever, decreased vaginal bleeding, minimal or no pain (AVS <4), leukocyte count within the normal range, evacuating and walking normally.

Follow-up All women included in the study will be reviewed within 7 days after discharge as routine at the gynecologic emergency unit, to receive the results of the pathology.

Outcomes

The following outcomes will be assessed:

1. Clinical improvement until discharge in number of days of hospitalization, complications related to treatment.

2. Treatment failure will be considered as persistence of fever (≥37.8ºC) during hospital admission, worsening of abdominal pain, persistent vaginal bleeding, need for exchange clindamycin due to treatment failure, or the need to add other antibiotics, either intravenously or orally.

3. Hospital readmission within 7 days after discharge due to fever (Tax ≥37.8ºC), persistent pelvic pain, persistence or increase of uterine bleeding, or other hospital admission related to the septic abortion.

4. Presence of urinary tract infection or candidiasis, persistence of ovular contents will not be considered as treatment failure.

Sample Size The sample size was calculated as a trial of non-inferiority, using the formula proposed in the literature (18). According to data obtained in a retrospective study by our group (16) we expect that the estimated rate of clinical cure is 99% (95% CI - 95 to 99%) in the group with three daily doses and 100% (95% CI - 99 to 100%) in the experimental treatment. For a non-inferiority study, using a power of 90%, an alpha error of 5% and a lower limit for non-inferiority of 2%, 95 cases will be needed in each group.

Statistical analysis Data will be analyzed by intention to treat and per protocol. The definition of intention to treat is based on the criteria suggested in the literature. The statistical analysis will be performed using Student t-test to compare the difference of means; chi-square test will be used to compare proportions with confidence intervals.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 190
• Est. completion date: December 2019
• Est. primary completion date: November 2019
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 13 Years to 50 Years

Eligibility

Inclusion Criteria:

• Women with clinical diagnosis of septic abortion

Exclusion Criteria:

• Refuse to participate in the study

• Use of antibiotics with 1 week prior randomization

• Known allergy to clindamycin or gentamcin

Related Conditions & MeSH terms

• Abortion, Septic
• Septic Abortion

Intervention

Drug:
• Clindamycin
Use of Clindamycin 2700mg+gentamicin 240mg+ 250ml sterile saline solution i.v. once a day or Gentamcin 240mg i.v once a day, plus clindamycin 900mg i.v. 8/8 h diluted in 250ml of sterile saline solution

Locations

Country	Name	City	State
Brazil	Hospital de Clínicas de Porto Alegre	Porto Alegre	Rio Grande Do Sul

Sponsors (1)

Lead Sponsor	Collaborator
Hospital de Clinicas de Porto Alegre

Country where clinical trial is conducted

Brazil, 

References & Publications (17)

Ahman E, Shah IH. New estimates and trends regarding unsafe abortion mortality. Int J Gynaecol Obstet. 2011 Nov;115(2):121-6. doi: 10.1016/j.ijgo.2011.05.027. Epub 2011 Aug 31. — View Citation

Blackwelder WC. "Proving the null hypothesis" in clinical trials. Control Clin Trials. 1982 Dec;3(4):345-53. — View Citation

Del Priore G, Jackson-Stone M, Shim EK, Garfinkel J, Eichmann MA, Frederiksen MC. A comparison of once-daily and 8-hour gentamicin dosing in the treatment of postpartum endometritis. Obstet Gynecol. 1996 Jun;87(6):994-1000. — View Citation

French LM, Smaill FM. Antibiotic regimens for endometritis after delivery. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD001067. Review. Update in: Cochrane Database Syst Rev. 2015;2:CD001067. — View Citation

Giugno CS, Silva AL, Fuhrich DG, Rabaioli PS, Gonçalves KG, Sartor NC, Savaris RF. Daily dose of clindamycin versus standard divided doses in obstetrical and gynecological infections: a retrospective cohort study. Int J STD AIDS. 2013 Nov;24(11):893-8. do — View Citation

Grimes DA. The "CONSORT" guidelines for randomized controlled trials in Obstetrics & Gynecology. Obstet Gynecol. 2002 Oct;100(4):631-2. — View Citation

Hemsell DL, Martens MG, Faro S, Gall S, McGregor JA. A multicenter study comparing intravenous meropenem with clindamycin plus gentamicin for the treatment of acute gynecologic and obstetric pelvic infections in hospitalized women. Clin Infect Dis. 1997 Feb;24 Suppl 2:S222-30. — View Citation

Hollis S, Campbell F. What is meant by intention to treat analysis? Survey of published randomised controlled trials. BMJ. 1999 Sep 11;319(7211):670-4. Review. — View Citation

Livingston JC, Llata E, Rinehart E, Leidwanger C, Mabie B, Haddad B, Sibai B. Gentamicin and clindamycin therapy in postpartum endometritis: the efficacy of daily dosing versus dosing every 8 hours. Am J Obstet Gynecol. 2003 Jan;188(1):149-52. — View Citation

Moberg PJ, Gottlieb C, Nord CE. Anaerobic bacteria in uterine infection following first trimester abortion. Eur J Clin Microbiol. 1982 Apr;1(2):82-6. — View Citation

Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW, Quintiliani R. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother. 1995 Mar;39(3):650-5. — View Citation

Plaisance KI, Drusano GL, Forrest A, Townsend RJ, Standiford HC. Pharmacokinetic evaluation of two dosage regimens of clindamycin phosphate. Antimicrob Agents Chemother. 1989 May;33(5):618-20. — View Citation

Rao SC, Srinivasjois R, Hagan R, Ahmed M. One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates. Cochrane Database Syst Rev. 2011 Nov 9;(11):CD005091. doi: 10.1002/14651858.CD005091.pub3. Review. Update in: Cochrane Database Syst Rev. 2016 Dec 06;12 :CD005091. — View Citation

Savaris RF, de Moraes GS, Cristovam RA, Braun RD. Are antibiotics necessary after 48 hours of improvement in infected/septic abortions? A randomized controlled trial followed by a cohort study. Am J Obstet Gynecol. 2011 Apr;204(4):301.e1-5. doi: 10.1016/j — View Citation

Singh S. Hospital admissions resulting from unsafe abortion: estimates from 13 developing countries. Lancet. 2006 Nov 25;368(9550):1887-92. — View Citation

Soper DE. Postpartum endometritis. Pathophysiology and prevention. J Reprod Med. 1988 Jan;33(1 Suppl):97-100. Review. — View Citation

Stubblefield PG, Grimes DA. Septic abortion. N Engl J Med. 1994 Aug 4;331(5):310-4. Review. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cure (Clinical improvement defined as reduce of pain, bleeding and no fever for 48h)	Clinical improvement defined as reduce of pain, bleeding and no fever for 48h Treatment failure will be considered as persistence of fever (=37.8ºC) during hospital admission, worsening of abdominal pain, persistent vaginal bleeding, need for exchange clindamycin due to treatment failure, or the need to add other antibiotics, either intravenously or orally.	72 hours
Secondary	Complications (Return to the hospital for admission related to the evacuation procedure within 7 days)	Return to the hospital for admission related to the evacuation procedure within 7 days	7 days