The incident happened on the northbound carriageway at around 6.50am between Leven viaduct and the A174, involving a Vauxhall Insignia, a Ford Focus, a FordTransit van, a Renault truck and a Toyota Corolla.
The 54-year- old female driver of a black Vauxhall Insignia was taken to James Cook University Hospital. She is currently in a stable condition.
A male passenger travelling in the same vehicle suffered a broken arm and multiple internal injuries and was airlifted to James Cook University Hospital. He is currentlyin a critical condition.
A 21-year- old male driver from the Toyota Corolla was taken to James Cook University Hospital with a broken back.
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The male drivers of the Ford Focus and the Renault Truck were checked over at the scene by paramedics and the male driver and passenger from the Ford Transit weretaken to hospital with leg injuries.
Officers closed the road whilst investigations took place into the incident.
Both carriageways were fully reopened at around 2pm.
Police say they would like to thank motorists for their patience whilst the incident was dealt with.
Anyone who may have seen the collision or anyone who may have sighted the black Vauxhall Insignia prior to the incident is asked to contact PC Ivan Hughes from the Cleveland and Durham Specialist Operations Unit, quoting event number 185526.