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Compassionate use of experimental treatments for Ebola virus disease: outcomes in 14 patients admitted from August to November, 2014.

Ebola virus disease is typically characterised by sudden onset of fever followed by severe diarrhoea and vomiting, and can have a mortality rate of up to 90%1. On 11 August 2014, an ethics panel convened by WHO concluded2 that it was ethical to offer non-registered experimental interventions to Ebola patients, conditional on the collection of evidence to inform the broader community on their efficacy. In order to fulfil this mandate, the WHO Secretariat began to collate data on patients given non-registered treatments, which in most cases were administered to individuals evacuated from West Africa to high-income countries, in an attempt to provide initial insight on the potential efficacy of new experimental treatments and inform the conduct of clinical trials.

As of May 2015 - 8 months after the milestone recommendations from the ethics panel - no consolidated report on the outcome of treatment with non-registered therapies is publicly available. The WHO Secretariat is therefore posting this short summary to inform the broader community.

The 14 patients included in this series were medically managed in France (Saint-Mandé), Germany (Frankfurt, Hamburg, Leipzig), Liberia (Monrovia), Norway (Oslo), Spain (Madrid), Switzerland (Geneva), and the United Kingdom (London). Data were collected using a standard letter and two questionnaires sent to treating physicians: the “minimal information for compassionate use form” and, since 6 October 2014 the ISARIC WHO Ebola Virus Disease form3.

Clinicians (in alphabetical order, Jose R. Arribas, Arne Broch Brantsæter, Thomas Grünewald, Michael Jacobs, Laurent Kaiser, Moses Massaquoi, , Christophe Rapp, Stefan Schmiedel, Timo Wolf) who provided data to WHO are gratefully acknowledged for their contribution. Krishnan Bhaskaran, Ph.D., London School of Hygiene and Tropical Medicine, London, United Kingdom, did all the analysis. Ana Maria Henao-Restrepo and Ximena Riveros, World Health Organization, Geneva, Switzerland, collected the data.

To quantify differences in case fatality between evacuated patients and those in the main epidemic area, each evacuated patient with known outcome (excluding the 3 treated with an investigational product in Liberia) were matched to 20 randomly selected patients with known outcome from the WHO database of confirmed and probable Ebola cases in Liberia, Sierra Leone, and Guinea, using data from the calendar period relating to the study population (July to November 2014). Statistical analyses were done in Stata version 13 (StataCorp, College Station, TX).

The confirmed Ebola patient population of 14 individuals received investigational treatment in Europe (n=11) or in Liberia (n=3). The majority (n=14) were health workers. Patients had a median age of 40 years (IQR 34-56), and were predominantly male (71%).

Most of patients received antipyretics, intravenous fluids and/or antibiotics as part of supportive care. 12/14 patients received one or more investigational treatments, as described in Table 1 below.

Table 1: Specific combinations used

 

 

ZMapp

Conv

Plasma

siRNA

Favi-piravir

Brinci-dofovir

ZMAb

 

X

 

 

 

 

 

4

X

X

 

 

 

 

1

 

X

 

X

 

 

1

 

 

X

X

 

X

2

 

 

 

X

 

 

2

 

 

 

X

X

 

1

 

 

 

X

 

X

1

 

 

 

 

 

 

 

Total (N patients receiving investigational treatment)

12

 

 

Most of the patients receiving investigational treatments (9/12) experienced some adverse reactions following treatment administration, though these cannot be definitively attributed to treatment given that with few exceptions patients were severely ill at treatment administration, and because of the small numbers involved. All four patients receiving ZMapp experienced transient fever after the first dose only; 3 additionally experienced tachycardia and 2 had reduced blood pressure. However, these reactions did not lead to treatment discontinuation.

4/14 patients (Table 2) died a median of 11 days after onset; overall case fatality 28.6%, 95% CI 8.4-58.1).

Table 2: Overall and stratum-specific outcomes and case fatality among the 14 patients with a definitive outcome

 

 

 

 

 

N

Died

% died (95% CI)

 

 

 

 

Overall

14

4

28.6 (8.4, 58.1)

 

 

 

 

By age (years)

 

 

 

      <50

9

0

0 (0, 33.6)

      ≥ 50

5

4

80.0 (28.4, 99.5)

 

 

 

 

By gender

 

 

 

      Male

10

4

40 (12.2, 73.8)

      Female

4

0

0 (0, 60.2)

 

 

 

 

By treatment

 

 

 

ZMapp

 

 

 

      Yes

5

2

40.0 (5.3, 85.3)

      No

9

2

22.2 (2.8, 60.0)

 

 

 

 

Convalescent plasma

 

 

 

      Yes

2

0

0 (0, 84.2)

      No

12

4

33.3 (9.9, 65.1)

 

 

 

 

siRNA

 

 

 

      Yes

2

0

0 (0, 84.2)

      No

12

4

33.3 (9.9, 65.1)

 

 

 

 

Zmab

 

 

 

      Yes

3

0

0 (0, 70.8)

      No

11

4

36.4 (10.9, 69.2)

 

 

 

 

Antiviralsa

 

 

 

      Yes

7

1

14.3 (0.4, 57.9)

      No

7

3

42.9 (9.9, 81.6)

 

 

 

 

 

aFavipiravir or Brincidofovir

11 of the 14 individuals treated in a high-income setting (i.e. excluding the 3 patients entirely managed in Liberia) could be matched on age and sex to up to 20 controls from the main epidemic in West Africa using data from the same calendar period (July 2014 or later). The odds of death were considerably lower among those managed in high-income settings (OR = 0.09, 95% CI 0.01 to 0.80).

Conclusion

This update presents data on 14 individuals with laboratory-confirmed Ebola who were treated with experimental therapies and/or in high-income settings during the 2014 outbreak. Mortality was considerably lower among these patients, compared with Ebola patients treated in West Africa. As expected, the large variety of treatment modalities used and the small numbers of deaths preclude any meaningful conclusions about association between use of specific experimental treatments and mortality. Clinical trials currently being conducted in West-Africa will hopefully provide definitive answers on the efficacy of the treatments.

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